Cytokinesis in Prokaryotes and Eukaryotes:
Common Principles and Different Solutions
Nanne Nanninga
Microbiol. Mol. Biol. Rev. 2001, 65(2):319. DOI:
10.1128/MMBR.65.2.319-333.2001.
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MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, June 2001, p. 319–333
1092-2172/01/$04.00⫹0 DOI: 10.1128/MMBR.65.2.319–333.2001
Copyright © 2001, American Society for Microbiology. All Rights Reserved.
Vol. 65, No. 2
Cytokinesis in Prokaryotes and Eukaryotes: Common Principles
and Different Solutions
NANNE NANNINGA*
Swammerdam Institute for Life Sciences, BioCentrum Amsterdam, University of Amsterdam,
1090 GB Amsterdam, The Netherlands
solved by the two groups of organisms. This will then serve as
an introduction to the (macro)molecular approach, which
forms the second part of this review. It will be seen that the
distinction between the cellular and macromolecular levels
cannot always be consequently maintained. The third part discusses the eukaryotic and prokaryotic solutions to the distribution of genetic material. In this respect it will become clear
that there are essential differences between prokaryotes and
eukaryotes. Of course, one can choose to emphasize or play
down the differences. In this review I will make the point that
these differences are important and that recent results as discussed here confirm this point of view.
Present research on cytokinesis is rapidly advancing, and
several model systems are being used. Animal systems include
mammals, Xenopus laevis, Drosophila melanogaster, and Caenorhabditis elegans. Somewhat resembling these systems is the
slime mold Dictyostelium discoidium. Yeasts and fungi repre-
INTRODUCTION
The cellular basis of life requires cytokinesis after DNA
replication and the distribution of the genetic material over
two new daughter cells (mitosis). To ensure that these daughter cells are genetically identical, nuclear division and cytokinesis must be well organized with respect to each other in time
and space. This comprises cellular logistics in prokaryotes as
well as eukaryotes, and it is this aspect of cytokinesis which is
the subject of this review.
This review consists of three parts. First, I will present a brief
overview of cytokinesis on the cellular and subcellular levels.
At the same time, I will highlight common problems to be
* Mailing address: Swammerdam Institute for Life Sciences, University of Amsterdam, P.O. Box 94062, 1090 GB Amsterdam, The
Netherlands. Phone: 31-20-525 5194. Fax: 31-20-525 6271. E-mail:
[email protected].
319
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INTRODUCTION .......................................................................................................................................................319
CYTOKINESIS AT THE CELLULAR AND SUBCELLULAR LEVELS............................................................320
Organization of the Bipolar Spindle Apparatus ................................................................................................320
Location of the Division Plane in Eukaryotes ....................................................................................................320
Location of the Division Plane in Prokaryotes...................................................................................................321
Preliminary Conclusions........................................................................................................................................321
CYTOKINESIS AT THE MACROMOLECULAR LEVEL ...................................................................................321
Cytokinesis and the Cytoskeleton.........................................................................................................................321
Cytokinetic ring...................................................................................................................................................321
Actomyosin and associated proteins ................................................................................................................321
Microtubules and SPBs .....................................................................................................................................322
Microtubule-associated motor proteins ...........................................................................................................323
Small GTPases and the cellular envelope .......................................................................................................323
IQGAPs ................................................................................................................................................................324
Bacterial Cytokinesis..............................................................................................................................................324
Cytokinesis in E. coli ..........................................................................................................................................324
Bipolar organization of the bacterial replicating chromosome....................................................................325
Chromosome segregation...................................................................................................................................326
Does DNA condensation play a role during chromosome segregation? .....................................................326
How does E. coli know where to divide? ..........................................................................................................326
DIFFERENT SOLUTIONS .......................................................................................................................................327
What Is the E. coli Equivalent of the Bipolar Spindle Apparatus?.................................................................327
Exploring the Poles.................................................................................................................................................328
Interaction of the Bipolar Spindle Apparatus with the Cell Envelope ...........................................................328
Cellular positioning of the BSA........................................................................................................................328
Role of small GTPases .......................................................................................................................................329
In the Center of the Bipolar Segregation Apparatus ........................................................................................329
Genesis of Bipolarization.......................................................................................................................................330
Evolutionary Aspects of Cytokinesis ....................................................................................................................330
FtsZ in chloroplasts and mitochondria ...........................................................................................................330
Evolution of FtsZ, ZipA, and FtsA into microtubules, MAPs, and actin? .................................................330
CONCLUSION............................................................................................................................................................330
ACKNOWLEDGMENTS ...........................................................................................................................................331
REFERENCES ............................................................................................................................................................331
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sent systems where the flexibility of cellular shape is limited by
a rigid, though not static, cell wall. These organisms also are
distinguished from animal systems by maintaining the nuclear
envelope during mitosis. The prokaryotic model organisms are
Escherichia coli, Bacillus subtilis, and Caulobacter crescentus.
Higher plants will not be discussed here, because they occupy
a somewhat different position.
CYTOKINESIS AT THE CELLULAR AND
SUBCELLULAR LEVELS
A precondition for the cell division process is the bipolar
organization of the cell. The first step toward attaining this
configuration is the duplication of the centrosome or microtubule-organizing center (MTOC). In higher eukaryotes, but also
in Dictyostelium, the MTOC is located near the nuclear envelope. In yeasts like Saccharomyces cerevisiae and Schizosaccharomyces pombe the MTOC is referred to as spindle pole body
(SPB). Their respective SPBs are quite different in structure
and composition. In S. cerevisiae the SPB is part of the nuclear
envelope, whereas in S. pombe it is located in the cytoplasm
during interphase and enters the nuclear envelope at the start
of mitosis. The various MTOCs all contain ␥-tubulin as part of
a microtubule-nucleating apparatus that facilitates radiation of
microtubules into the cytoplasm (for a review, see reference
86).
Centrosomes and the SPB of S. pombe duplicate at the
beginning of mitosis; in S. cerevisiae duplication occurs at the
beginning of S phase (for reviews, see references 6 and 37).
After duplication, one of the MTOCs moves to a diametrically
opposite position in the cell. The early SPB duplication in S.
cerevisiae with respect to S. pombe, might be required for the
movement of the nucleus into the growing bud (see below).
At the onset of mitosis, microtubules become arranged between the MTOCs. Because the nuclear envelope disintegrates
during mitosis in higher eukaryotes, the inter-MTOC microtubules are in direct contact with the cytoplasm. By contrast, the
nuclear envelope in yeasts persists, thus preventing intracellular contacts of the inter-MTOC (SPB) microtubules beyond
the nuclear envelope (unless the nuclear pores serve a communicating function [see below]). Despite minor differences,
the essential elements of a bipolar spindle organization, here
referred to as the bipolar spindle apparatus (BSA), are shared
among all eukaryotes.
Location of the Division Plane in Eukaryotes
In most eukaryotes the division plane becomes located halfway between the MTOCs of the BSA. Displacement of the
BSA by centrifugation in Crepidula eggs was accompanied by
displacement of the cleavage plane (Fig. 1a) (reference 91 and
references therein). This classic experiment by Conklin has
emphasized the potential importance of the cellular envelope
region halfway between the MTOCs. Subsequent research has
also revealed the importance of astral microtubule-mediated
interaction with the nearest cell cortex for BSA positioning in
the cell (for a review, see reference 101) (see below).
In S. cerevisiae, division site selection is a direct consequence
of bud site selection (14). Thus, to place the predetermined
FIG. 1. Position of the BSA relative to the site of cytokinesis. (a)
Animal cell. In the right-hand cell, the BSA has been shifted to the
periphery by pressing a glass bead onto the mitotic cell. (b) S. cerevisiae. The elongating nucleus positions itself relative to the neck of the
growing bud (thick double arrows). (c) S. pombe. Medial ring positioning follows the predetermined site of the nucleus. MT, microtubules.
division plane halfway along the BSA, the nucleus itself has to
be moved in a proper orientation in the cell (13) (Fig. 1b). This
leads to the question of how the mitotic nucleus becomes
properly oriented in a budding cell. A likely mediator is the
SPB because it connects the inner and outer surface of the
nuclear envelope. Inside the nucleus, the mitotic spindle elongates between the SPBs. Outside the nucleus, astral microtubules radiate to the opposite plasma membrane in the growing
bud. Notably, in S. cerevisiae the interaction of astral microtubules with the opposing plasma membrane has been demonstrated (107). Eventually, the BSA orients toward a preexisting
septum marker, the bud site (Fig. 1b).
By contrast, in S. pombe the division site must be established
in relation to the cellular position of the nucleus (Fig. 1c) (13).
To do this, a mechanism can be expected which maintains the
nucleus in the cell center. Presumably this is achieved, at least
in interphase, through the microtubular framework which surrounds the nucleus (38). It can be imagined that this frame-
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Organization of the Bipolar Spindle Apparatus
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properly oriented in the cell. However, bacteria lack MTOCs,
and therefore there must be a bacterial equivalent of the eukaryotic MTOC.
The above outline is rather general. Below I will embark on
a molecular description of cytokinesis in bipolar cells. For
eukaryotes this refers to the role of the dynamic cytoskeleton
and its many associated proteins. For prokaryotes we need to
find whether there is a cytoskeleton-like equivalent.
CYTOKINESIS AT THE MACROMOLECULAR LEVEL
FIG. 2. Cell cycle phases in a prokaryote and in a eukaryote. In a
prokaryote, the bacterial chromosome does not condense prior to
segregation. The chromosome separates during its replication. Therefore, the S phase coincides with the M phase. G1, cell cycle phase prior
to DNA replication. In E. coli, this phase is denoted B. Its occurrence
depends on the strain and on growth conditions. G2, phase between
termination of DNA replication and mitosis. This phase is not present
in E. coli. S, DNA replication phase.
work also interacts with the plasma membrane, thus positioning the nucleus at a defined position in the cell.
In essence, this representation of the two yeasts is not different from that of a cleaving higher eukaryotic cell. In all
cases, the final spatial orientation is the same: a defined orientation of the division plane perpendicular to the BSA. What
differs is the way in which this orientation is achieved.
Location of the Division Plane in Prokaryotes
Early light micoscopic data have shown that the E. coli
division plane is positioned between segregated chromosomes
and halfway between the cell poles (70, 104). DNA compaction
after completion of replication, as generally occurs during eukaryotic mitosis, has so far not been demonstrated in bacteria.
In fact, there is no need for such a phase because, as demonstrated previously (104) and studied in E. coli in particular, the
replicating chromosome becomes distributed over the prospective daughter cells during elongation of the cell (for reviews,
see references 32, 103, and 125). E. coli therefore does not
have a separate M phase. This is depicted schematically in Fig.
2, where the prokaryotic and eukaryotic cell cycle phases are
compared.
Preliminary Conclusions
The comparison of cytokinesis of eukaryotes and prokaryotes at the cellular and subcellular levels can be summarized as
follows. (i) Before cytokinesis, a BSA is formed in eukaryotes.
(ii) Orientation of the BSA is facilitated by astral microtubules
that interact with the opposing cortex or cell envelope. (iii) The
cleavage plane has a defined position between the MTOCs.
(iv) S. cerevisiae deviates in the sense that the BSA adjusts its
position with respect to the predetermined cleavage site; in all
other cases discussed here, the reverse is true. (v) In prokaryotes, cytokinesis occurs halfway between the cell poles. As in
eukaryotes, the replicated bacterial chromosome must become
Cytokinetic ring. Cytokinesis in eukaryotes is achieved by a
contractile ring associated with the plasma membrane. The
ring basically consists of actin and myosin II, and the actomyosin organization resembles that of smooth muscle (for a review, see reference 101). In nondividing cells this ring is absent,
and its establishment involves extensive spatial reorganization
of the actin filament-based cytoskeleton. Apart from the contractile ring and its association with the cell cortex, the microtubules and the microtubule-associated proteins in the spindle
interzone have been invoked as instrumental in the cytokinetic
process (for reviews, see references 28 and 101). It is not my
aim to compare in detail the cytokinetic process in different
eukaryotes; rather, I will attempt to provide an overall “eukaryotic picture.” Doubtless this picture will be basic. However, by focusing on the main aspects, a comparison with prokaryotic cytokinesis will be facilitated. It will be appreciated
that the circumference of the cytokinetic ring of E. coli is
considerably smaller than its eukaryotic counterpart. Even in a
small eukaryote like D. discoidium, there is a 100-fold difference (Fig. 3). In addition, the macromolecular composition of
the E. coli cytokinetic ring is essentially different.
As mentioned above, two main components of the cytoskeletal framework, actomyosin complexes and microtubules, and
their respective associated proteins play a vital role in eukaryotic cytokinesis. Broadly speaking, microtubules help in positioning of the bipolar BSA in the cell and actin filaments are
essential for the septation process. An additional feature of
eukaryotic cytokinesis is the involvement of members of the
Rho family of small GTPases in establishing a local interaction
between the cytoskeleton and the plasma membrane. In yeasts
this applies to the cell wall, and in higher eukaryotes it applies
to the extracellular matrix. It will be seen that although the cell
wall is instrumental in carrying out prokaryotic cytokinesis,
Rho-like GTPases are probably not involved.
Actomyosin and associated proteins. In fungi as well as
animal cells, actomyosin complexes play a role in carrying out
the septation process. Since such complexes are also present
elsewhere in the cell before cytokinesis, the localized rearrangement of the actomyosin network is an important prerequisite for division. Many other actin binding or actin-associated
proteins localize to the septum or cleavage plane. One group of
such components are septins.
In S. cerevisiae, septins are part of a network in the neck of
the bud underneath the plasma membrane (11). Septins are
indispensable for septation and form a scaffold for the assembly of the actomyosin complex (for reviews, see references: 27,
62, 65, and 88). Several septins have been found in S. cerevisiae,
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FIG. 3. Cytokinetic rings in a eukaryote and a prokaryote. In the
highly schematized eukaryote, the cytokinetic ring is represented by a
vertical white bar. In the prokaryote, E. coli, a cell division protein,
FtsQ, has been labeled by its fusion to green fluorescent protein
(GFP). Note the difference in the sizes of the two cells. (Copyright T.
den Blaauwen and J. Chen.)
and some of these proteins have also been found in other
eukaryotes, including animals. Septins show GTPase activity,
although the functional significance of this observation is still
unclear (27).
In S. pombe, a Mid1p ring precedes the actin ring. However,
whereas the Mid1p ring arises independently of the actin ring,
both are dependent on actin-associated proteins (108). Interestingly, Mid1p localizes to the nucleus in interphase, suggesting that it leaves the nucleus and then forms a ring at the onset
of mitosis (108). This fits, but does not explain, the observation
that the central position of the nucleus is important in establishing the site of cytokinesis in S. pombe (38, 39). This location
makes sense because in eukaryotes that maintain the nuclear
envelope during mitosis, it is the nucleus that has to be located
relative to the site of septation and not the mitotic spindle. By
contrast, when the nuclear envelope is broken down, spindle
components might directly interact with the medial cortex.
The number of proteins being discovered that bind actin
(Abp proteins), apart from myosins, is steadily increasing,
which not only stresses the importance of the actomyosin network but also points to the complexity of the regulation of its
functioning.
Microtubules and SPBs. Of the three classes of spindle
microtubules, namely, kinetochore-bound microtubules, centrosome-connecting microtubules, and astral microtubules, the
last, because of their interaction with the cortex, have received
the most attention recently. This interaction makes the cortex
perhaps a prime determinant of the bipolar organization of
the cell. Two examples, in S. cerevisiae and S. pombe, underline
this.
In S. cerevisiae, elegant in vivo studies have been carried out
FIG. 4. Interaction between microtubules and growing poles in
S. cerevisiae and S. pombe. (a) In S. cerevisiae, astral microtubles explore the
poles while the nucleus moves into the bud. The motor protein dynein travels
along microtubules and pulls at the dynactin molecules at the cell cortex.
Reprinted from reference 12 with permission of the publisher. (b) Growing
microtubules deposit Tea1p at the poles. Adapted from reference 69, with
permission of the publisher, MT, microtubules.
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with microtubules containing a green fluorescent protein GFP–␣tubulin fusion protein (12) or with microtubules labeled with a dynein-GFP fusion (107). These experiments showed the dynamic instability and orientation of microtubules emanating from an SPB in
the developing bud (Fig. 4). The searching behavior of the growing
astral microtubules ultimately resulted in a defined placement of the
BSA in the cell.
In S. pombe, in early mitosis the future septation site is
already marked through the formation of the medial ring between the duplicated SPBs (for a review, see reference 34).
This ring also contains microtubule components (87) (see below). However, medial ring positioning (in contrast to nucleus
positioning) is not dependent on intact microtubules (108).
Interestingly, longitudinally arranged microtubules appear to
be associated with specific proteins at the extreme ends of
interphase cells (Fig. 4). One of these proteins is Tea1p (tip
elongation aberrant), which, when mutated, produces T-shaped
cells. It has therefore been suggested that Tea1p is required for
maintaining the normal rod shape of S. pombe (68). A similar
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323
FIG. 5. The Rho-GTPase molecular switch. The conformation of
the GTPase depends on whether GTP or GDP is bound. The GTPbound form functions through an effector. This interaction is abolished
when GTP is hydrolyzed with the aid of GAP. A guanine nucleotide
exchange factor (GEF) catalyzes the production of active Rho-GTP.
Adapted from reference 41.
function in establishing cell polarity for focused bud growth
and septation. This polarizing effect requires dynamic rearrangement of the actomyosin cytoskeleton toward the plasma
membrane, to which Cdc42p is attached through a membrane
anchor. The activity of Cdc42p is modulated by a GEF (Cdc24p)
as well as by GAPs (Bem3p and Gga1p) (for a review, see reference 88). Activated Cdc42p stimulates yeast homologs of
p21-activated kinases (PAKs) such as Ste20p and Cla4p (22),
which in turn phosphorylate myosin II heavy-chain head domains. In this example, the myosin II heavy chain was isolated
from Dictyostelium whereas the kinases were purified from
yeast (Ste20p and Cla4p) and rat brain (PAK) (reference 128
and references therein). Note that S. pombe contains myosin II
heavy chains in the actomyosin ring (50).
Remarkably, myosin II appeared dispensable in substrateanchored Dictyostelium cells, whereas this was not so for cells
in suspension. It has been speculated that the extent to which
polar regions of a dividing cell are fixed affects the establishment of a “proper gradient of cortical tension” as required for
cytokinesis (for a review, see reference 30).
In Xenopus embryos, the GTPases Rho and Cdc42 promote
furrow ingress during cytokinesis. Whereas Rho appeared to
be involved in the organization of the actin cytoskeleton, the
role of Cdc42 was less clear. In the latter case, the possibility
was raised that Cdc42 interacts with the septin network (20).
The role of Rho in Xenopus cytokinesis is reminiscent of the
earlier observation that fibroblast Rho is instrumental in the
assembly of focal adhesions (96).
The interaction of cytoplasmic components with the plasma
membrane is of particular importance, because the plasma
membrane has to contract with the aid of an actomyosin machinery. Not surprisingly, lipid components also appear to affect the organization of the actomyosin skeleton. For instance,
in Xenopus extracts actin assembly could be induced by phosphoinositides in the presence of small GTP-binding proteins
(64) (see below). Similarly, phosphatidylinositol-4,5-biphosphate appeared to dissociate actin-Abp complexes (gelsolin) in
permeabilized human platelets, thus allowing polymerization
of actin into a subcortical actin network. The Abp proteins also
mediate the interaction with the plasma membrane (integrins)
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suggestion has been made for Pom1p, a kinase, which localizes
to the cell poles as well as the septum (3). Tea1p localization
does not require Pom1p, whereas Pom1p needs Tea1p, suggesting that Pom1p acts downstream of Tea1p at the cell poles
(3). Tea1p persists at the poles during mitosis, whereas the
microtubules at the two poles shrink (68). Whether subsequent
astral microtubules become associated with Tea1p during mitotic anaphase has not yet been studied. In fact, the interaction
of astral microtubules with the polar cortex region in living
S. pombe has received less attention than in S. cerevisiae (however, see reference 17). Very recently, a kinesin-like protein,
Tea2p, has been detected at the cellular poles (8). Tea1p localization appeared dependent on Tea2p, and one speculation
was that Tea1p represents cargo for the motor protein (Tea2p)
to be transported to the cell poles along microtubules (8).
Protein kinases that localize to the SPB as well as to the
medial ring have been detected in S. pombe. Examples include
a polo-like kinase Plo1p (4); an IQGAP-related protein, Rng2p
(23) (see below); and an SPB kinase, Sid2p (109). The dual
localization of these proteins has been interpreted to mean
that the SPB functions as a signaling site for cytokinesis, presumably with the aid of microtubules (reference 108 and references therein). It would thus seem that the interphase organization of the microtubular framework, including polar
interactions, contributes to the positioning of the nucleus in
the cell center at the onset of mitosis.
Microtubule-associated motor proteins. It is well known that
microtubules serve as roadways for plus-end-directed (kinesins) and minus-end-directed (dyneins) motor proteins, thus
allowing a polarized arrangement and transport of cellular
components. Astral microtubules presumably interact with the
cortex in animal cells with the aid of minus-end-directed proteins (for reviews, see references 2 and 61). As mentioned above,
such interaction has also been implied for the astral microtubules in the the growing bud of S. cerevisiae (Fig. 4) (107).
The astral microtubule-cortex interaction in animal cells is
thought to predetermine the cellular position of the BSA and
eventually the location of the cleavage plane (for a review, see
reference 101). As pointed out above, the medial cortex becomes irreversibly committed to cytokinesis (even in the absence of a BSA), provided that astral microtubule-cortex contact lasted long enough (for a review, see reference 92).
Small GTPases and the cellular envelope. Small GTP-binding proteins and heterotrimeric G proteins represent molecular switches that influence numerous processes related to the
dynamic cellular organization (2, 61). The monomeric small
GTPases include subfamilies such as Ras and Rho (41). Their
functioning as switches is based on general principles. Basically, the switch involves an alternation between two conformational states which are defined by the binding of either GTP
or GDP. Nucleotide binding is affected by activators, effectors,
and inhibitors, which in turn are influenced by additional components. In the example shown in Fig. 5 (“Ras protein paradigma” [41]), the GTP-bound form activates an effector. Inactivation occurs through hydrolysis of GTP, resulting in the
inactive GDP-bound form. In vivo hydrolysis is controlled by
GTPase-activating proteins (GAPs). The GTP-bound form
arises through a GDP-GTP exchange reaction, which is catalyzed by a guanine nucleotide exchange factor.
In S. cerevisiae, Rho small GTPases include Cdc42p and they
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Bacterial Cytokinesis
FIG. 6. Domain composition and homology of IQGAP-related
proteins from various organisms. The percentages refer to the conservation of domain composition compared to mammalian IQGAP1. CH,
calponin homology domain; IR, internal repeats; WW, SH3-mimicking
domain; IQ, calmodulin binding motifs; GRD, RasGAP-homology
domain. For further details, see reference 65. Adapted from reference
65 with permission of the publisher.
at focal adhesions, which influences the organization of the
extracellular matrix in animal cells (2, 61). Until now, the
extracellular matrix has received little attention as a possible
factor in cytokinesis. By contrast, the yeast equivalent of the
extracellular matrix, the cell wall, is clearly instrumental in
effecting cytokinesis. The same consideration applies to prokaryotes.
Rho1p of S. cerevisiae is involved in the regulation of cell
wall synthesis, because it activates 1,3-␤-glucan synthase, which
makes a major polymer (1,3-␤-glucan) of the yeast cell wall
(21, 89). Rho1p, like Cdc42p, also regulates the reorganization
of the actin cytoskeleton, which in the former case is accomplished by the interaction with the actin-binding protein profilin as mediated through Bni1p and Bnr1p (46).
This brief survey indicates that the regulation of the organization of the actin skeleton toward the plasma membrane
and beyond (cell wall and extracellular matrix) is in principle
conserved in a variety of lower and higher eukaryotes.
IQGAPs. A cytokinetic role of IQGAP-like proteins has
been demonstrated so far for D. discoideum, S. cerevisiae, and
S. pombe. These proteins were first discovered in humans (82,
120) and were first considered to be GAPs (for a recent review,
see reference 65). IQGAPs contain a number of domains (Fig.
6), which include CH (calponin homology domain which putatively binds to actin), IQ (calmodulin-binding motifs) and
GRD (GAP-related domain) domains. IQGAP-like proteins
have been found in other organisms, but the extent to which
the different domains have been retained varies considerably
(65). Whereas the D. discoideum IQGAP possesses only the IQ
and GRD domains, the S. cerevisiae and S. pombe IQGAP-like
proteins resemble the human protein in organization.
Cytokinesis in E. coli. Traditionally, cytokinesis has been
termed cell division in prokaryotes. In E. coli, division is basically a constriction process, whereas in B. subtilis, there is an
ingrowing septum like that in S. pombe. Constriction in E. coli
involves three envelope layers, which are, from outside to inside, the outer membrane, the peptidoglycan layer, and the cell
membrane. The peptidoglycan layer is embedded in the socalled periplasm and serves as an exoskeleton to the bacterial
cell. Its local synthesis at the site of constriction is indispensable for the division process, as are cytoplasmic polymers (for
reviews, see references 43 and 76) (see below).
Several proteins are known that are specifically involved in
the division process (for reviews, see references 63, 66, 76, and
99). All of them have been detected as temperature-sensitive
mutants that filament at the nonpermissive temperature, and
therefore many of the proteins have the prefix Fts. The majority of the Fts proteins are anchored to the cell membrane;
their main domains protrude into the cytoplasm or into the
periplasm (Fig. 7).
All cell division proteins were previously localized to the
site of division by fluorescence microscopy (Fig. 3). The use of
appropriate mutants and microscopy has likewise resulted in a
tentative temporal assembly line of the division apparatus,
called the divisome. Assembly of the divisome starts with the
positioning of an FtsZ ring in the cell center. The ring is
FIG. 7. Topology of E. coli cell division proteins relative to the
plasma membrane. The numbers in the molecules reflect the molecular masses in kilodaltons. With the exception of FtsK and FtsW, the
membrane-bound proteins contain a single membrane anchor. The
way in which the various proteins interact with each other is not
known. pm, plasma membrane; pg, peptidoglycan. Reprinted from
reference 76a with permission of the publisher.
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In D. discoideum, the IQGAP-like protein GAPA appeared
to be required for the completion of cytokinesis, because myosin II was still deposited in the cleavage furrow in a gapA mutant (1). Also, in S. cerevisiae gene disruption of the IQGAPlike gene (Cys1/Iqg1) allowed the formation of a myosin
II-containing ring (58). However, accumulation of actin filaments in the cytokinetic ring appeared to be Cyk1p/Iqg1p dependent (24, 58). These observations fit the idea that IQGAPs
play a role in cellular actomyosin architecture, presumably (at
least in part) through the GRD domain. It has also been
suggested that IQGAPs interact with Cdc42p to establish actomyosin ring assembly (23, 58).
VOL. 65, 2001
stabilized by FtsA and ZipA (Z-interacting protein A) (40, 73).
Subsequently, FtsK, FtsW, FtsQ, FtsL, and FtsN become recruited to the cytokinetic ring (for a review, see reference 66).
The number of Fts proteins per divisome is on the order of
thousands for FtsZ, and on the order of hundreds or even less
for most of the others. Thus, presumably, the cytokinetic FtsZ
ring is composed of an FtsZ backbone to which other Fts
proteins are attached at a limited number of sites, thus forming
divisome subassemblies (Fig. 8).
In recent years, increasing attention has been focused on the
cytoplasmic division protein FtsZ (for reviews, see references
26 and 66). It is a GTPase and can polymerize in vitro as well
as in vivo into filamentous polymers. FtsZ bears structural
resemblance to eukaryotic tubulin (for a review, see reference
24). However, microtubular structures composed of FtsZ have
not been detected in prokaryotes. Little is known about the
function of most of the division proteins. An exception is FtsI,
which is a penicillin-binding protein, also denoted PBP3 (for a
review, see reference 77). It plays a role in division-specific
peptidoglycan synthesis. As a consequence, components of the
peptidoglycan-synthesizing machinery may be present in the
divisome. Division-specific peptidoglycan synthesis starts almost simultaneously with the positioning of FtsZ near the cytoplasmic membrane at the cell center (16), suggesting a tight
link between cytoplasmic FtsZ polymerization and periplasmic
peptidoglycan synthesis (75). The chemical nature of the link is
not known.
What is the cytokinetic motive force? A contractile mechanism based on an actomyosin-complex, like that in eukaryotes,
appears unlikely in prokaryotes. Motor proteins such as myosins, kinesins, and dyneins have not been convincingly detected
in E. coli. Since the diameter of the E. coli divisome decreases
during division, it appears plausible that regulated depolymerization of the FtsZ ring is an important agent, next to the
ingrowing leading edge of the peptidoglycan layer. In B. subtilis, a protein, EzrA, has been identified that modulates the
frequency and position of FtsZ ring formation (55). It has
325
therefore been suggested that EzrA plays a regulatory role in
FtsZ depolymerization during ring contraction.
Bipolar organization of the bacterial replicating chromosome. Mitosis in eukaryotes is an active process, encompassing
dynamic cytoskeletal structures and various motor proteins. It
even can proceed in a cell-free system (2, 61). By contrast, the
small size of a bacterium (Fig. 3) has precluded a description of
its partitioning apparatus in macromolecular terms. It also
explains why progress in this field has been made only very
recently (see below). It should be remembered that E. coli as
well as B. subtilis has a circular genome which replicates bidirectionally from a fixed origin of replication toward the socalled terminus diametrically opposite the origin. This situation is quite different from that of eukaryotes, where there are
many origins per chromosome and where defined termini are
probably not present (Fig. 9). So far, for prokaryotes a dominant view has been that the interaction of the bacterial chromosome with the elongating cell envelope is instrumental in
separating newly replicated chromosomal domains.
Recent reports based on fluorescence microscopy images of
labeled DNA segments or of proteins closely associated with
the origin of replication did, however, suggest that prokaryotes
(E. coli [33, 78, 81, 97], B. subtilis [31, 57, 119], and C. crescentus [47, 71]) contain a bipolar partitioning apparatus. This was
deduced from the dynamic behavior of the duplicated origin of
replication. The terminus of DNA replication in E. coli has
also been localized, and its cellular position could be compared
with that of the origin. At one stage of DNA replication, for
instance, the origins had moved apart whereas the terminus
still persisted at the future site of division (33, 78, 81).
In E. coli, the more or less constant distance of the bacterial
chromosome (115) and of the origins of replication (78, 97) to
the cell poles has been interpreted to mean that replicating
chromosomes move apart coincident with cell elongation (96,
122). By contrast, time-lapse images of fluorescent foci com-
FIG. 9. Replicating eukaryotic and prokaryotic (E. coli) chromosomes. A eukaryotic chromosome contains numerous bidirectional
replicating units, each containing its own origin of replication. E. coli
replication starts at a defined origin and proceeds bidirectionally. An
E. coli chromosome does not contain a centromere or telomeres.
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FIG. 8. Schematic representation of the FtsZ ring and its associated subassemblies. The subassemblies are supposed to contain proteins involved in peptidoglycan synthesis in addition to the cell division
proteins depicted in Fig. 7. Reprinted from reference 76 with permission of the publisher.
CYTOKINESIS IN PROKARYOTES AND EUKARYOTES
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which affects chromosome segregation, as witnessed through
dispersion of nucleoid structure and the formation of DNAless cells in temperature-sensitive mukB mutants (reference 80
and references therein). It occurs as a homodimer in the cell
(79) and, like its eukaryotic counterpart, is a rod-like molecule
with globular ends (reference 70 and references therein). The
N-terminal part resembles dynamin and can bind ATP and
GTP, whereas the role of the C-terminal part is less clear (79).
MukB can also bind DNA. It should be mentioned that the
structure of MukB resembles that of SMCs, whereas its amino
acid sequence does not (70).
Recently, it was shown that the N-terminal part of MukB
(containing the nucleotide-binding domain) can bind to polymerized FtsZ in the presence of GTP (60). This suggests that
chromosome segregation includes a MukB-mediated connection between DNA and the FtsZ ring. However, immunofluorescence microscopy of MukB revealed its confinement to the
nucleoid and not to the FtsZ ring (T. den Blaauwen et al.,
submitted for publication).
The B. subtilis SMC-like protein Smc bears more sequence
resemblance to its eukaryotic counterparts than does MukB
(70). Like MukB, it affects chromosome segregation (8, 72),
and immunofluorescence microscopy has shown that it occurs
at poles and near the nucleoid (8, 35). Its cellular location,
therefore, does not coincide with that of MukB in E. coli.
Are there prokaryotic condensins and cohesins? It should
be stipulated that prokaryotes (including archaebacteria) sequenced until recently contained either a single smc gene or
none at all (for a review, see reference 42). This suggests that
in prokaryotes a condensin-cohesin function, if it occurs, may
reside in one and the same multiprotein complex. Interestingly,
recent evidence showed that MukB forms a complex with
MukE and MukF (130). However, the notion that bacterial chromosomes segregate while being replicated (32, 122) precludes a
cohension function, at least in E. coli. Likewise, there is no evidence that bacterial chromosome become compacted in the same
way as required for eukaryotic mitosis (however, see below). The
location of MukB in the nucleoid (den Blaauwen et al., submitted) and the dispersion of the nucleoid in mukB mutants
(80) suggest a nucleoid-scaffolding function for MukB, as has
also been suggested for condensin in eukaryotic mitotic chromosomes (reference: 5 and references therein). In fact, as
shown recently, negative supercoiling of the E. coli nucleoid
appeared to be reduced in a mukB mutant (121). In line with
this observation, suppression of the mukB phenotype occurred
through a mutation in topA (encoding topoisomerase I), which
led to excess negative supercoiling (102). MukB may aid the
chromosome segregation process by local DNA condensation,
thus providing a pulling action on the replicating nucleoid.
How does E. coli know where to divide? The simple question
of how E. coli knows where to divide has generated much
speculation. One view is based on the observation that cytokinesis takes place between duplicated nucleoids when they are
sufficiently separated (nucleoid occlusion). Thus, the location of
the division plane is directly related to the cellular position of the
replicating bacterial chromosome (74, 124). Whereas the original
nucleoid occlusion model was based on observing cellular constrictions as such, recent studies have confirmed that the positioning of the FtsZ ring is affected by the nucleoid in a similar
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posed of GFP-LacI fusions bound to tandem lac operators at
specific chromosomal sites in E. coli (33) and in B. subtilis (118)
have indicated that these foci can move independently of cell
elongation. Foci of labeled proteins which colocalize with the
origin of replication of B. subtilis (the ParB-like Spo0J protein
[56]) also separate in conjunction with the duplicated origin
independently of cell elongation (31). This has been interpreted to mean that an active agent (“mitotic-like” [31, 106])
helps in separating the nascent daughter chromosomes.
It would thus seem, that genes occupy a cellular position
according to two levels of organization. On one level, their
position is linked to the chromosome partitioning process, in
the sense that the replicated origins and nearby genes are
arranged in a bipolar fashion. On the other level, genes might
move within the confinement of a nucleoid compartment (98).
Chromosome segregation. Once decatenated, how do the
duplicated chromosomes assume their new positions in the
prospective daughter cells and how does FtsZ ring formation
correlate with bacterial chromosome partitioning? It has been
found that, within experimental error, FtsZ-ring formation in
E. coli coincides with termination of DNA replication (16).
Because the nucleoid borders (115) as well as the duplicated
oriC origins (78, 97) maintain a constant distance from the cell
poles in an elongating cell, the question can be asked whether
the replicated termini become pushed apart by an active mechanism. Conceptually, one could invoke cytoplasmic components and/or the invaginating cell envelope. For FtsZ, the
indications for a role in chromosome partitioning are twofold.
First, a delay in nucleoid segregation has been inferred in
FtsZ-depleted cells (113), and second, nucleoid segregation
appeared affected in an ftsZ temperature-sensitive mutant at
the nonpermissive temperature (45; C. L. Woldringh, personal
communication). Evidence for an envelope role also arose
from the interesting observation that separation of the replicated chromosomes is delayed in an ftsI temperature-sensitive
mutant at the nonpermissive temperature (45, 110) or after
impairment of FtsI (PBP3)-specific peptidoglycan synthesis by
specific penicillins (45). This suggests that division-specific envelope synthesis contributes to the partitioning of daughter
chromosomes. Perhaps the above-mentioned role of FtsZ in
chromosome partitioning is indirect, because it is plausible that
impairment of membrane-associated FtsZ affects division-specific peptidoglycan synthesis.
Another actor possibly involved in DNA segregation is the
largest cell division protein, FtsK (147 kDa) (Fig. 7). Its N-terminal part is needed for localization at midcell (19, 59, 116,
131), whereas its C-terminal might play a role in DNA segregation (59). The C-terminal part of FtsK resembles the B. subtilis protein SpoIIIE (59), which is thought to act during the
transfer of spore DNA to the mother cell (129).
Does DNA condensation play a role during chromosome
segregation? Like eukaryotes, prokaryotes possess structural
maintenance of chromosomes (SMC) proteins. In eukaryotes,
these proteins are involved in mitotic chromosome condensation and in chromatid cohesion. These activities are carried out
with the help of other proteins, and the complexes have been
termed condensin and cohesin, respectively. In these multiprotein complexes, different SMCs are present and occur as heterodimers (for reviews, see references 5, 42, and 70).
The E. coli SMC-like protein, MukB, is a 177-kDa protein
MICROBIOL. MOL. BIOL. REV.
VOL. 65, 2001
CYTOKINESIS IN PROKARYOTES AND EUKARYOTES
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DIFFERENT SOLUTIONS
What Is the E. coli Equivalent of the Bipolar
Spindle Apparatus?
way (36, 112). The observed coincidence of termination of DNA
replication and FtsZ ring formation (16) also fits the model.
The selection of the division plane has achieved a new dimension through the observation of oscillation of GFP-labeled
MinC (44), MinD (94, 100), and MinE (29) between the two
cellular poles (Fig. 10). These proteins have acquired the prefix
Min because when they are mutated, polar divisions occur that
produce DNA-less minicells. Thus, E. coli contains three potential division sites, the central one and one at each pole.
According to a model (15), the combination of MinCD inhibits
polymerization of FtsZ at potential division sites unless MinE
is present. That is, under wild-type conditions, MinE prevents
the inhibition of FtsZ polymerization at the cell center. In line
with the model, a MinE ring has been observed at the cell
center, independent of FtsZ (93).
As pointed out by Raskin and de Boer (94), the abovementioned Min protein-based oscillator(s) might serve as a measuring device leading to the definition of the cell center. Note
that the timescale of the oscillations is on the order of minutes,
showing that they take place many times during a division cycle.
Is there a link between nucleoid occlusion and MinE ring
positioning? MinE-GFP rings have been observed on top of
nucleoids, whereas this was not the case for FtsZ rings in parallel samples (112). Since FtsZ polymerization is inhibited by a
combination of MinC and MinD (and relieved by MinE) and
also by the presence of a nonsegregated nucleoid, it has been
suggested that FtsZ ring assembly is subject to two negative
topological regulators (112). Finding how these regulators interact will be a great challenge.
To the best of my knowledge, a cell pole-to-cell pole oscillator has not been described for eukaryotic cells. It will be
important to know whether such an agent reflects a general
princple in a cell’s search for its prospective site of fission.
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FIG. 10. Time-lapse images in seconds (numbers) of GFP-MinD
oscillations in living E. coli cells. Fluorescent GFP-MinD appears as
bright polar regions. The cells to the right were imaged with differential interference contrast. For details, see reference 94 (reprinted with
permission of the publisher).
Mitosis in eukaryotic cells requires DNA compaction into
discrete chromosomes after the cells have traversed through
the S and G2 cell cycle phases. In prokaryotes, no distinction
can be made between interphase and mitosis. DNA segregation goes hand in hand with replication (122, 125, 127). Therefore, prokaryotes have no mitosis in the classical (eukaryotic)
sense (Fig. 2). Even so, this does not detract from the concept
that cytokinesis in prokaryotes requires a bipolar cellular arrangement of the replicating or replicated chromosome.
How can the macromolecular differences be assessed? I will
start with the well-known eukaryotic situation and enumerate
some perhaps obvious aspects (2, 61). (i) DNA replication
occurs through numerous origins (Fig. 9). (ii) After completion
of DNA replication, the sister chromosomes (chromatids) stay
together until mitotic anaphase. (iii) The replication origins
play no role in chromatid separation. (iv) Chromatid separation is preceded by integral chromosome compaction. (v) A
bipolar spindle apparatus is formed in between duplicated
MTOCs. (vi) Sister chromosome separation requires the dissolution of a so-called cohesin complex (reference 117 and
references therein) (vii) Chromatid segregation is effected by
shortening of microtubules between the kinetochore and MTOC.
(viii) The kinetochore binds to specific nucleotide sequences
(centromere).
I will now list, with some generalization, the prokaryotic solution. (i) DNA replication occurs through one origin only
(Fig. 9). (ii) The bacterial “chromatids” do not stay together;
they move apart during the DNA replication process. (iii) Nucleotide sequences near the origin of replication provide binding sites for proteins that may assist in DNA separation, i.e., in
maintaining a constant distance of the origin to the cell pole
(note that B. subtilis is an exception [105]). (iv) No microtubules
or kinetochores are present in bacteria. (v) Apart from SMClike proteins, classical motor proteins resembling myosin, dynein, and kinesin have not yet been detected in prokaryotes.
As suggested above, one can consider the origin of replication and/or associated proteins to be the eukaryotic centromere analogue (reference 33, and references therein). The
prokaryotic terminus of DNA replication would then be the
equivalent of the telomere. In a general mechanistic sense, this
appears plausible. However, in macromolecular terms, this
comparison does not hold. Eukaryotic origins of DNA replication play no role in mitosis, and telomeres have no functional
relationship to the prokaryotic terminus of replication.
The bacterial analogue of the MTOC is more difficult to
define. During mitosis, centromeres (while bound to kinetochores) approach MTOCs. Does the E. coli origin of replication, as a centromere analogue, approach something? Because
the average distance of duplicated oriC origins from the cell
poles remains constant during most of the DNA replication
cycle while the cell elongates (78, 97), the cellular poles might
be considered the MTOC analogues. Consequently, according
to this reasoning, the E. coli centromere analogue (oriC) and
its MTOC analogue (the cellular pole) coincide. However, it
has also been shown that individual GFP-labeled gene regions
can move independently of cell elongation (reference 33 and
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MICROBIOL. MOL. BIOL. REV.
Interaction of the Bipolar Spindle Apparatus
with the Cell Envelope
FIG. 11. Comparison of cell wall extension in S. pombe and in E.
coli. S. pombe extends at the poles, presumably aided by the polarized
microtubular framework. In E. coli, the poles are inert with respect to
cell wall extension and cell elongation takes place between the poles.
Here the poles are not connected through a cytoskeletal structure in
the cytoplasm. A diffusible component oscillates between the poles
instead. MT, microtuble. For further details, see the text.
see above), which suggests some autonomy with respect to the
mobility of subcompartments of the segregating nucleoid. On
the other hand, the E. coli nucleoid as a whole seems to separate along with cell elongation (115). Thus, globally, it would
seem that the replicating and simultaneaously segregating bacterial chromosome, with its origins directed toward the cell
poles, represents the E. coli equivalent of the BSA.
Cellular positioning of the BSA. In previous sections I have
mentioned the interplay of eukaryotic cytoskeletal elements
with the envelope (cortex, plasma membrane, and cell wall) of
the cell. These interactions referred to the behavior of astral
microtubules while connecting the separating MTOCs to the
nearest cortex and to the cytokinesis process as such in the cell
center. All these interactions will serve to confine the eukaryotic BSA in its proper cellular position. What keeps the bacterial chromosome in its place in the absence of eukaryotic
cell-like cytoskeletal structures?
It has been hypothesized that the confinement of the nucleoid is the result of the balancing of two opposing forces (123).
On the one hand, compaction is achieved by DNA supercoiling, DNA-binding proteins, and phase separation of cytoplasm
and nucleoplasm (126); on the other hand, DNA transcription
at the cytoplasmic surface of the nucleoid is thought to loosen
its structure, in particular when DNA loops are directed to the
cytoplasmic membrane by the process of coupled transcription,
translation, and membrane protein insertion (123) (Fig. 12).
Exploring the Poles
Comparison of E. coli and S. pombe with respect to polarity
and envelope extension will also serve to illuminate basic structural differences between prokaryotes and eukaryotes (Fig. 11).
Cell wall extension in S. pombe occurs at the poles, either at
one or at two poles (for a review, see reference 48). Presumably, building blocks of the growing poles are carried to their
destination with the aid of a microtubule-based transport system. As mentioned above, Tea proteins might direct microtubules to their proper polar location. By contrast, E. coli poles
are largely inert and envelope extension takes place through
intercalation of peptidoglycan precursors in the lateral wall
(for reviews, see references 43, and 76). Here, gene products
needed for envelope assembly (membrane-anchored PBPs)
find their way through coupled transcription-translation-membrane insertion. It might be speculated, that in the latter case
the topological arrangement of genes being transcribed is directly related to the pattern of envelope assembly (10, 76) (Fig.
12). Clearly, the spatial separation of transcription and translation by a nuclear envelope precludes this possibility in a
FIG. 12. Cotranslational insertion of membrane proteins in the
plasma membrane of E. coli. OM, outer membrane; PM, plasma membrane. (Copyright C. L. Woldringh.)
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eukaryote. In fission yeast, directionality of cell wall assembly
is probably aided by a polarized cytoskeleton.
In S. pombe, microtubules are arranged in such a way that
their positive ends point to the respective poles. The presumed
structural communication between the poles might thus be
mediated through a defined cellular structure (Fig. 4). How
does E. coli fit in this scheme?
In the absence of a classical cytoskeleton in E. coli, i.e., one
located in the cytoplasm, it is not immediately clear how polar
communication is achieved or whether it is at all relevant.
However, as mentioned in a previous section, recent evidence
has shown that MinC and MinD can oscillate between poles
(Fig. 10). It would thus seem that the absence of a cytoskeleton
in a small prokaryote is compensated for by an oscillation
mechanism presumably based on protein diffusion.
VOL. 65, 2001
This would mean that DNA transcription loops serve as structural mediators between the nucleoid and the envelope. In
fact, the temporal association of these loops with the elongating rod-shaped cell has been invoked as a mechanism to
achieve the gradual separation of the replicating bacterial
chromosome (Fig. 13) (123).
Is there a bacterial equivalent for astral microtubules? In
E. coli, the distances of the duplicated origins of replication
(78, 97) and of the nucleoid borders (115) to the cell pole
remain more or less constant during the cell cycle. How are this
constant distances maintained? One can think of a protein
framework attached to the origin of replication or to regions
flanking the origin, which extends toward the cell poles. The
protein composition of this putative framework is unknown,
although one might think of proteins that can form protofilaments, at least in vitro. One might consider FtsZ and EF-Tu
(the E. coli ribosomal elongation factor) as potential components. These two components are abundant proteins, with
many more molecules present than would be required for cell
division or protein synthesis, respectively (reference 76 and
references therein). Note that transcription loops as potential
structural mediators (Fig. 12) are probably not in contact with
the polar envelope. The reason is that the poles are considered
inert with respect to envelope synthesis, since this process
takes place at the lateral sides (Fig. 11).
In E. coli, proteins involved in peptidoglycan assembly are
part of the divisome (43, 75, 76). One of these proteins is FtsI,
and it was mentioned above, that impairment of this protein
delays nucleoid separation (45). Interaction of the E. coli BSA
with the cellular envelope is thus twofold: (i) a constant distance is maintained between the origin region and the cell
pole, and (ii) defects in cell division proteins affect nucleoid
segregation.
Role of small GTPases. In a previous section, membraneanchored Rho-like GTPases were mentioned as mediators between the eukaryotic cytoskeletal organization and assembly of
the cell envelope, be it the extracellular matrix or the cell wall.
An example was Rho1p of S. cerevisiae, which is involved in
activation of 1,3-␤-glucan synthase (21, 89) and also in the
reorganization of the actin cytoskeleton (46). So far, the only
known protein of the E. coli divisome exhibiting GTPase activity is FtsZ. However, tubulin-like FtsZ does not belong to
the group of Rho-like GTPases.
With respect to switches in E. coli, the “Ras paradigma”
329
does not seem to apply. E. coli response regulator proteins,
which are part of so-called two-component regulatory systems,
function as switches through protein phosphorylation and dephosphorylation in this organism. An example is the regulation
of chemotaxis. Whether such two-component regulatory systems play a role in E. coli cytokinesis is not clear. However,
evidence is accumulating for a the existence of a transcription
factor (CtrA) in C. crescentus which functions as a cell cycle
transcriptional regulator. Cell cycle-dependent processes like
DNA replication, DNA methylation, and flagellar biosynthesis
appear to be controlled by CtrA in this organism (90). Later, it
was found that increases in cellular CtrA concentration reduced ftsZ transcription whereas decreases led to the opposite
effect (49). Whether a similar global cell cycle regulator functions in E. coli is not known.
In the Center of the Bipolar Segregation Apparatus
To allow redistribution of duplicated chromosomes over the
new daughter cells, chromosomes become aligned in the center
of the BSA during eukaryotic metaphase. In E. coli, as discussed above, this refers to the distribution of genes rather
than to that of chromosomes. In the classic model of DNA
replication, the polymerase holoenzyme travels around the circular chromosome in two directions. Alternatively, as originally proposed by Sueoka and Quinn (111) and by Dingman
(18), the DNA to be replicated passes through a stationary
structure or replisome. The term “replisome” has been defined
as a supramolecular assembly “with helicases, primosome, and
polymerase holoenzyme operating coordinately at the replication fork” (52). Indeed, recent experiments indicate that DNA
replication takes place in the cell center (in E. coli [51] and B.
subtilis [53, 54]). It should be mentioned that the idea of a local
FIG. 14. Bipolarization in a eukaryote and in a prokaryote. In a
eukaryotic cell, the compacted chromosomes are arranged in the metaphase plate, which is symmetrically located between the MTOCs. In a
prokaryote like E. coli, the replisome is symmetrically located between
the duplicated origins (oriC). In this representation, the oriC region of
the chromosome and associated proteins are analogues of the MTOC.
However, in E. coli, no distinction can be made between the centromere and MTOC functions. Note also that the chromosomes have
completed replication in the metaphase plate whereas it is the replisome, active in DNA replication, that is centrally located.
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FIG. 13. Schematic model of E. coli nucleoid segregation. The
nucleoid is transiently connected to the plasma membrane through transcription loops. The model refers to slowly growing cells, where segregation takes place in the long axis of the cell. Reprinted from reference 127 with permission of the publisher.
CYTOKINESIS IN PROKARYOTES AND EUKARYOTES
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NANNINGA
aggregation of replisomes had already gained some popularity
in the eukaryotic field some time ago (85). Of course, in this
case the fixed replisome has no relevance for the central position of the metaphase plate. However, a central cellular position of the prokaryotic replisome would collect the genes to
be replicated in the cell center before being distributed over
the new daughter cells. In this sense, the prokaryotic replisome
is the analogue of the eukaryotic metaphase plate (Fig. 14).
Genesis of Bipolarization
Evolutionary Aspects of Cytokinesis
Evolution of cytokinesis can be considered on two levels of
cellular organization. First, it can be asked whether the eukaryotic cytokinetic ring evolved from its prokaryotic counterpart. Second, it could be asked whether chloroplasts and mitochondria fission in a prokaryotic way. This question arises
because according to the endosymbiosis hypothesis, these organelles are of prokaryotic origin. I will start with the latter
topic (for reviews, see references 26 and 84).
FtsZ in chloroplasts and mitochondria. Initial attempts to
find FtsZ in mitochondria have met with little success. By
contrast, in chloroplasts of Arabidopsis thaliana two types of
FtsZ proteins have been found. They are nucleus encoded; one
of them, FtsZ1, appears to be located in the stroma of the
chloroplast, whereas the other one, FtsZ2, occurs the outside
of the chloroplast (83). It has been suggested that FtsZ1 would
be equivalent to the prokaryotic FtsZ in aiding constriction
whereas the external FtsZ2 would carry out a squeezing role
(26). In this sense, FtsZ2 would assume a role which in grampositive and gram-negative bacteria is performed by the ingrowing peptidoglycan (75, 76).
Very recently, FtsZ has been detected in mitochondria of a
lower eukaryote, the brown alga Mallomonas splendens (7). In
mitochondria of yeasts and higher eukaryotes, fission, in the
absence of FtsZ, is accomplished with the aid of dynamin (26,
84).
As mentioned in a previous section, MukB from E. coli and
SMC-like protein from B. subtilis each contain a domain that
resembles dynamin. In E. coli, MukB and FtsZ do interact
(60), suggesting that MukB is, one way or another, involved in
bacterial cytokinesis. One might speculate that in the course of
evolution, the loss of FtsZ provided for a more dominant role
of dynamin-like proteins in the fission of eukaryotic organelles.
Evolution of FtsZ, ZipA, and FtsA into microtubules, MAPs,
and actin filaments, respectively? Until now, little, if anything,
was known about the evolution of the eukaryotic cytokeleton.
Because of the resemblance of FtsZ to tubulin, it has often
been suggested that microtubuli arose from FtsZ (reference 25
and references therein). Interestingly, ZipA (Fig. 7) appears to
contain sequence elements in its N-terminal cytoplasmic domain resembling those of eukaryotic microtubule-associated
proteins (MAPs) (95). In vitro, ZipA was found to promote
bundling of FtsZ protofilaments (95), thus strengthening its
MAP resemblance. Whereas FtsZ is present in all prokaryotes
studied so far (for a review, see reference 66), ZipA does not
seem to occur in gram-positive bacteria and archaebacteria,
suggesting that in these cases other proteins might have acquired a similar role (95). Of course, these findings have not
yet elucidated how the prokaryotic FtsZ ring evolved into a
eukaryotic spindle apparatus for the separation of replicated
chromosomes. One clue linking FtsZ to chromosome segregation might be, as mentioned above, that impairment of FtsZ
affects the segregation of completed chromosomes in E. coli
(45, 113).
Another component of the E. coli divisome, FtsA, has recently been crystallized from the thermophilic eubacterium
Thermotoga maritima (114). This protein bears a strong resemblance to actin and could therefore be the predecessor of actin
in the eukaryotic cytokinetic ring (114).
In the eukaryotic cytokinetic system, motor proteins interact
with microtubules and actin filaments whereas motor proteins
are sparse in prokaryotes. As a speculation, MukB, resembling
dynamin, might have been an example for motor proteins to
develop.
CONCLUSION
Cytokinesis requires duplication of cellular structures followed by bipolarization of the predivisional cell. As a common
principle, this applies to prokaryotes as well as eukaryotes.
However, the macromolecular mechanisms to achieve this are
essentially different. As pointed out above, duplication of a
eukaryotic origin of DNA replication, as well as its genome,
does not suffice to establish a bipolar cell. It requires the
duplication of the MTOC as a prelude to mitosis, and it is here
that the dynamic cytoskeleton with all its associated proteins
comes to the fore. Eukaryotes, because of their size, have thus
created a higher level of organization, where the MTOC has
taken over the segregating function of the prokaryotic origin of
replication.
In prokaryotes, a cytoskeleton that pervades the cytoplasm
appears to be absent. DNA replication and the concomitant
DNA segregation seem to occur without the help of extensive
supramacromolecular assemblies. Prokaryotic cytokinesis, however, proceeds through a contracting ring, which has a roughly
100-fold-smaller circumference than its eukaryotic counterpart. Its macromolecular composition is also essentially different, although it contains proteins that can be considered predecessors of actin, tubulin, and MAPs.
Downloaded from http://mmbr.asm.org/ on February 27, 2014 by PENN STATE UNIV
How does bipolarization arise? It obviously needs the duplication of something, and it is directly related to the duplication
of the genetic material. In E. coli, duplication of the origin of
replication is the first step. Subsequently, the two origins move
apart during cell elongation. In this way, bipolarity is created in
E. coli.
By contrast, duplication of a eukaryotic genome does not
suffice to establish a bipolar cell. Duplication of the MTOC is
required as a prelude to mitosis, and it is here that the dynamic
cytoskeleton comes to the fore. Eukaryotes have thus created
a higher level of organization, where the MTOC has taken over
the putative segregating function of the prokaryotic origin of
replication and its associated proteins (Fig. 14). As mentioned
above, in E. coli DNA strands become distributed over new
daughter cells, whereas in eukaryotes this applies to a set of
sister chromatids.
MICROBIOL. MOL. BIOL. REV.
VOL. 65, 2001
CYTOKINESIS IN PROKARYOTES AND EUKARYOTES
ACKNOWLEDGMENTS
I am very grateful to Frans Hochstenbach, Moselio Schaechter,
Conrad Woldringh, and Marco Roos for critically reading the manuscript and for making suggestions.
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CYTOKINESIS IN PROKARYOTES AND EUKARYOTES