MINIREVIEW
Protein quality control in time and space – links to cellular
aging
€ m & Beidong Liu
Thomas Nystro
Department of Chemistry and Molecular Biology, Göteborg University, Göteborg, Sweden
€m,
Correspondence: Thomas Nystro
Department of Chemistry and Molecular
Biology, Gothenburg University,
€teborg,
Medicinaregatan 9C, 413 90 Go
Sweden. Tel.: +46 31 786 2582;
fax: +46 31 786 2599;
e-mail: [email protected]
Received 10 June 2013; revised 15 July 2013;
accepted 6 September 2013. Final version
published online 11 October 2013.
DOI: 10.1111/1567-1364.12095
Editor: Dina Petranovic
Abstract
The evolutionary theory of aging regards aging as an evolved characteristic of
the soma, and proponents of the theory state that selection does not allow the
evolution of aging in unicellular species lacking a soma–germ demarcation.
However, the life history of some microorganisms, reproducing vegetatively by
either budding or binary fission, has been demonstrated to encompass an
ordered, polar-dependent, segregation of damage leading to an aging cell lineage within the clonal population. In the yeast Saccharomyces cerevisiae and the
bacterium Escherichia coli, such segregation is under genetic control and
includes an asymmetrical inheritance of protein aggregates and inclusions.
Herein, the ultimate and proximate causation for such an asymmetrical inheritance, with special emphasis on damaged/aggregated proteins in budding yeast,
is reviewed.
Keywords
asymmetrical inheritance; spatial protein
quality control; replicative aging.
YEAST RESEARCH
Introduction
The evolutionary theory of aging highlights the importance of the soma–germ demarcation and that the body
(somatoplasm in Weismanns original theory; Weismann
et al., 1891) lives for only one generation, whereas hereditary material (‘anlagen’ in the ‘germ plasm’; Weismann
et al., 1891) is immortal and passed from generation to
generation (Weismann et al., 1891; see also, e.g. Medawar, 1952; Williams, 1957; Kirkwood, 1977; Rose, 1991;
Gladyshev, 2013). This demarcation leads to differential
requirements for maintenance and homeostasis: germ
cells must be optimized for youthfulness, whereas the
soma, or individual, in a sense is disposable and serves as
the ‘steward’ of the germ line (Kirkwood, 1977, 2005). In
the germ plasm, both hereditary material and cytosolic
functions must be preserved and damage prevented from
being transmitted to the offspring. Protecting the germ
cells from cytosolic damage may be accomplished by different principal means, including preservation mechanisms (Fig. 1) in which the germ cells enjoy an elevated,
or more functional, homeostatic maintenance system
eliminating any damage that may arise (Kirkwood &
Holliday, 1979). Other possible preservation mechanisms
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Published by John Wiley & Sons Ltd. All rights reserved
include an asymmetrical partitioning of cytosolic damage
during gametogenesis, or a selection process, that rids the
organisms of germ cells exhibiting high levels of damage
(Sheldrake, 1974; Holliday, 1975; Medvedev, 1981). It has
also been suggested that germ cells are provided with
superior means of eliminating damage, but are only doing
so upon fertilization and embarking on embryonic development (Hernebring et al., 2006, 2013). In the latter scenario, resources for damage elimination are only fully
invested in the cells that will become progeny, which
might be a cost-effective means of rejuvenation (Fig. 1).
In addition, during cell fate specification of mouse
embryonic stem cells, this elimination of protein damage
is dependent on the PA28 activator of the proteasome,
which, in contrast, to the 26S proteasome, acts in the
absence of ubiquitin tagging and ATP hydrolysis (Hernebring et al., 2013), again an economical means of damage
control for rejuvenation.
Regardless of the mechanisms being involved, the key
issue is that there is a division of labor between the aging
somatic cells and the ‘immortal’ germ cells. A question
that arises is whether such division of labor is restricted
to organisms with a soma–germ delineation or whether
unicellular organisms have evolved similar strategies.
FEMS Yeast Res 14 (2014) 40–48
41
Protein quality control and aging
Preservation
Soma
Aging lineage
Germ cells
Opposite sex
Germ cells
”Immortal lineage”
Rejuvenation
Soma
Aging lineage
Germ cells
”Immortal lineage”
Fig. 1. Schematic models of preservation and rejuvenation of the germ line. In the germ line preservation model (left), cells (germ cells) having
the potential to become the offspring are persistently maintained in a pristine condition and protected from damage. In this model, the somatic
cells of the organism age, while the germ cells do not. In contrast, in the rejuvenation model (right), damage (red dots) might accumulate in
both germ cells and the soma. However, upon fertilization, for example, during early embryogenesis, the potential of damage elimination is set
into action, and the damage load is reset. Note that these models are not mutually exclusive and may be different for different type of
organisms, damages, and molecules (e.g. DNA and proteins) being affected.
Experimental evidence suggests that some microbial
species do, and Jazwinski (Jazwinski, 1993; Jazwinski
et al., 1998) has proposed a model for how such a division of labor (epigenetic stratification) can provide a
selective advantage for a clonal cell population of a unicellular organism. Herein, we will summarize the evidence
for such a division of labor with special emphasis on the
temporal and spatial control of damaged proteins and
discuss to what extent these examples call for an amendment of the evolutionary theory of aging. Before doing
so, a short overview of the evolutionary theory of aging is
presented.
The evolutionary theory of aging at a
glance
Most animals in their natural habitat die at young age
due to, for example, diseases, accidents, and predation.
Therefore, very few ‘old’ adults ever reproduce and give
rise to offspring. From this, it follows that the forces of
natural selection decline with age, and genes beneficial
early in life are favored over genes beneficial late in life –
there is little evolutionary advantage in having beneficial
genes at an age that only an infinitesimal fraction of the
population will ever reach (e.g. Medawar, 1952; Rose,
1991). By the same token, an allele that causes accelerated
deterioration of the soma at an advanced age, which few
individuals of that particular species attain, will have little
impact on the fitness of the organisms bearing it, and
such alleles cannot be selected against (Williams, 1957;
Rose, 1991). A prediction from the theory, then, is that
animals in particularly hazardous environments need to
FEMS Yeast Res 14 (2014) 40–48
favor rapid development and optimize early reproduction,
which is followed by relatively rapid aging of the soma.
In contrast, less perilous environments allow for delayed
development/reproduction and a slower rate of somatic
deterioration (Kirkwood, 1977; Luckinbill & Clare, 1985;
Rose, 1991; Austad, 1993, 1997; Sgro & Partridge, 1999;
Kirkwood & Austad, 2000).
Within the framework of the evolutionary theory of
aging, two supplementary population genetic mechanisms
of somatic aging have been proposed: antagonistic pleiotropy (Williams, 1957) and mutation accumulation
(Medawar, 1952). The latter theory argues that the process of aging is due to the accretion over long periods of
time of many late-acting deleterious mutations, which, as
described above, cannot be selected against (Medawar,
1952; Charlesworth & Charlesworth, 2000). In the theory
of antagonistic pleiotropy, Williams (1957) (see also
Hamilton (1966) and Ljubuncic & Reznick (2009)) argues
that pleiotropic mutations that cause accelerated aging (as
a byproduct) might, in fact, be selected if they increase
the fitness of the young individuals. Thus, their beneficial
early-acting effects on reproductive success offset their
late-acting deleterious effects on the soma.
Whereas the mutation accumulation and antagonistic
pleiotropy theories are based on population genetics, the
‘disposable soma’ theory finds its arguments in physiological ecology and emphasizes that acquisition of greater
longevity comes at a cost (Kirkwood, 1977; Kirkwood &
Rose, 1991; Drenos & Kirkwood, 2005). The theory suggests that due to resource limitations and the competing
demands of reproduction and maintenance, fewer
resources are devoted to somatic maintenance than is
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42
required for immortality. Further, the pressures of the
environment dictate how resources are optimally distributed, or traded, between reproduction and maintenance –
hazardous environments are predicted to lead to rapidly
developing organisms and a relatively large input of
resources into early reproduction. The trade-off for this
investment into reproduction is a reduced somatic maintenance and a relatively rapid deterioration/aging of the
soma. There are several examples of, and mechanisms for,
nutrient-responsive trade-offs between reproduction and
maintenance also in unicellular organisms (Nystrom,
2002, 2003, 2004a, b; Ferenci, 2005; Gummesson et al.,
2009), highlighting that such trade-offs are not restricted
to ‘late’- and ‘early’-acting alleles in organisms with a
soma distinct from the germ line.
The demarcation between the soma and germ line is a
cornerstone in the evolutionary theory of aging, and as
stated by Williams, ‘The theory regards aging as an
evolved characteristic of the soma. We should find it
wherever a soma has been evolved, but not elsewhere’
(Williams, 1957). Rose (1991) makes the point even more
explicitly stating that ‘in cases of strictly vegetative reproduction, selection does not allow the evolution of aging’
and that ‘this is one of the strongest theoretical predictions in all of evolutionary biology’. However, the fact that
the life history of some vegetatively reproducing, unicellular, microorganisms – both prokaryotic and eukaryotic –
encompasses mandatory aging appears to call for a
reappraisal of the evolutionary theory of aging. In addition, evidence for unicellular populations being agestructured supports the hypothesis that asymmetric division and epigenetic stratification may be mechanisms
underlying, and being required for, microbial culture
immortality (Jazwinski, 1993; Jazwinski et al., 1998).
Indeed, several computational approaches have shown that
differentiation between an aging parental cell and a rejuvenated progeny readily evolves to cope with self-inflicted
damage and that asymmetrical segregation of irreparable
damage may permit survival of the clone at the expense of
the ‘mother-type’ cells (Johnson & Mangel, 2006; Watve
et al., 2006; Ackermann et al., 2007; Erjavec et al., 2008).
In line with these theoretical considerations, it has been
proposed that the evolution of aging was first contingent
on the development of polarization and a division of labor
between mother-type and daughter-type cells in clonal
populations of unicellular microorganisms rather than the
separation of soma from germ line (Ackermann et al.,
2003; Erjavec et al., 2008; Macara & Mili, 2008).
It should be noted that the inclusion of unicellular
organisms as members of the exclusive club of aging
organisms does not, in fact, challenge the crucial arguments of the evolutionary theory. Because of the simple
arithmetic of vegetative, exponential reproduction, old
ª 2013 Federation of European Microbiological Societies.
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€m & B. Liu
T. Nystro
mother cells (like old animals) are extremely rare in the
population and the forces of natural selection therefore
impotent in affecting ‘late’-acting alleles. Thus, the concept of the disposable soma (Kirkwood, 1977) and antagonistic pleiotropy (Williams, 1957) theories of aging can be
directly applied to, and tested on, unicellular systems that
display replicative aging. In contrast, the mutation accumulation theory is conceptually more difficult to use in
explaining unicellular aging (or more specifically, cellular
rejuvenation), provided age-related mutations are fixed
and inherited. However, an interesting possibility is that
mutations accumulating during replication and the division event are asymmetrical leading to a differential spectrum of genome alterations in the mother and daughter
cells. There is, in fact, an evidence for that this is the case
during yeast budding (McMurray & Gottschling, 2003),
but it is presently unclear whether this asymmetry impacts
on aging and daughter cell rejuvenation.
In summary, the life history of some unicellular organisms encompasses lineage-specific aging, and theoretical
and mathematical arguments have been presented as to
why such aging, as a byproduct, might be beneficial for
preventing clonal senescence. Next, we will review the
nature of this microbial aging phenomenon, with special
emphasis on protein quality control and the proximate
causation of this control.
Mandatory aging in yeast and bacteria
Microorganisms have proven useful models for elucidating
specific molecular/physiological mechanisms underlying
antagonistic pleiotropy and regulatory trade-offs (Nystrom,
2002, 2003; Ferenci, 2005) and for approaching particular
proximal hypotheses of aging, such as the error catastrophe
theory (e.g. Orgel, 1963; Gallant & Palmer, 1979), and the
free radical hypothesis of aging (Dukan & Nystrom, 1998;
Dukan et al., 2000; Ballesteros et al., 2001; Nystrom, 2005).
However, it should be noted that the senescence
approached in such studies is of a conditional nature; that
is, it is the die-off of cells observed when one or several
required nutrients become exhausted/limited, and cell proliferation is arrested. This is a form of death triggered by
debilitating alterations in the environment, which is conceptually distinct from mandatory aging in higher organisms. Therefore, the term ‘conditional senescence’ was
proposed to make this distinction clear (Nystrom,
2004a, b; Fredriksson & Nystrom, 2006).
In addition to conditional senescence, however, the life
history of some species of unicellular organisms has been
shown to encompass mandatory aging, and Saccharomyces
cerevisiae is the most well-studied microorganism displaying such aging. The term ‘mandatory aging’ is used here
to underscore that the mother cell, regardless of keeping
FEMS Yeast Res 14 (2014) 40–48
43
Protein quality control and aging
S. cerevisiae
Virgin cell
Mother
Daughter
“Aging lineage”
”Immortal lineage”
C. cresentus
Stalked cell
Swarm cell
“Aging lineage”
”Immortal lineage”
E. coli
Old pole
Old pole
Old pole
”Immortal lineage”
“Aging lineage”
FEMS Yeast Res 14 (2014) 40–48
conditions optimal for its reproduction, will eventually
stop generating daughter cells and subsequently lyse. During the progressive divisions and replicative aging, the
mother cell undergoes many changes, including a prolonged generation time, decline in mating ability, accumulation of toxic extrachromosomal genetic material
(Sinclair & Guarente, 1997) and reactive oxygen species
(Laun et al., 2001), increased oxidative damage to proteins (Aguilaniu et al., 2003), formation of protein aggregates (Erjavec et al., 2007), alterations in mitochondrial
function and morphology (Lai et al., 2002; Scheckhuber
et al., 2007; Veatch et al., 2009), increased mitochondrial
fragmentation (Scheckhuber et al., 2007; Veatch et al.,
2009; Hughes & Gottschling, 2012), and a switch to a
hyperrecombinational state (McMurray & Gottschling,
2003). With the exception of the latter study, which deals
with diploid yeast cells, most of the aging characteristics
have been studied in haploid strains, and it should be
noted that the aging phenotype of haploid and diploid
strains may differ due to, for example, differential expression of mating type characteristics (Guarente, 2000).
One of the first events seen very early during replicative
aging is a decline in vacuolar pH control, and some of
the later events of aging, notably mitochondrial fragmentation and dysfunction, are a direct consequence of the
early collapse in vacuolar function (Hughes & Gottschling, 2012). Such results highlight the decidedly interconnected nature of homeostatic machineries, which makes
them vulnerable to perturbations as the breakdown of
one specific homeostatic process during aging or stress
brings forth repercussions on other maintenance activities. However, in spite of such a sequential decline in
homeostatic control systems, mother cells, if not too close
to their terminal state (Kennedy et al., 1994), generate
offspring exhibiting a full replicative potential, and the
acquired aging phenotypes of the mother cell are thus
prevented from being inherited by the progeny during
the process of asymmetrical division (Jazwinski, 1996).
This asymmetrical cytokinesis encompasses an unequal
inheritance of toxic and deteriorated material, such that
extrachromosomal rDNA circles (ERCs) (Sinclair & Guarente, 1997; Shcheprova et al., 2008), oxidatively damaged
proteins (Fig. 2; Aguilaniu et al., 2003; Erjavec &
Nystrom, 2007), and protein aggregates (Erjavec &
Fig. 2. Mandatory replicative aging and delineation of aging and
immortal cell lineages in unicellular systems. The drawing depicts the
three unicellular models demonstrated to display lineage-specific aging.
In the yeast and Escherichia coli, models, accumulation of damaged/
aggregated proteins (red dots) is associated with the aging cell lineage,
whereas no such data presently exist on the Caulobacter model.
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44
Nystrom, 2007; Erjavec et al., 2007; Liu et al., 2010,
2011) are retained in the mother cell during cytokinesis.
Among bacteria, Caulobacter crescentus was the first
species reported to exhibit mandatory replicative aging
(Ackermann et al., 2003). Like S. cerevisiae, C. crecentus
divides asymmetrically – during each division, the bacterium produces a motile swarmer cell and a stalk cell. The
swarmer cell, which is equipped with a flagellum, differentiates into a stalk cell after swimming for a limited
period of time. Ackermann et al. (2003) found that with
each division, the stalked cell requires progressively longer
times to produce a swarmer cell, a manifestation of lineage-specific replicative aging (Fig. 2). At present, however,
it is not known whether damage retention/accumulation
is underlying aging of the stalked cells.
Escherichia coli is the second bacterial species reported
to display replicative aging (Stewart et al., 2005). In contrast to C. crescentus, E. coli divides by binary fission and
lacks a sibling-specific differentiation. Stewart et al.
(2005) calculated the generation time of individual cells
and found, intriguingly, that the growth rate decreases
progressively in cells inheriting old poles. Subsequently, it
was shown that protein aggregates accumulate upon cell
division in the aging cells with older poles (Fig. 2;
Lindner et al., 2008). Apparently, bacteria, like yeast, segregate protein aggregates into an aging cell lineage while
leaving the other, rejuvenated, lineages free of such
damage.
The question has been raised as to whether it is possible
to extrapolate the data and assume that the reduction in
sibling-specific growth rate will eventually cause the bacterial cell to die It has been argued that if variabilities of
E. coli cell length and age at division are taken into
account, the sibling-specific decreases in growth rate fall
within the expected variation and are sufficiently different
from the catastrophe-like cell death arrived at through
replicative aging (Woldringh, 2005). A counterpoint was
made pointing out that the growth rate of old pole E. coli
cells becomes progressively slower during the repeated
divisions studied, suggesting that the results are due to an
ordered ‘aging-type’ phenomenon rather than random
variation (Stewart & Taddei, 2005). To make matters more
complex, however, when cell growth was analyzed for
E. coli old pole cells using microfluidics, the authors found
that growth rate did not slow down with repeated generations (Wang et al., 2010). Nevertheless, it was suggested
that the mortality of E. coli cells in such a population is
not stochastic, but the result of accumulating damage,
such as protein aggregates (Wang et al., 2010). If so,
E. coli cells are distinct from other aging models studied
in that they can accumulate damage without any effects
on fitness (cellular growth rate) until they suddenly, and
cataclysmically, die of such damage (Wang et al., 2010).
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€m & B. Liu
T. Nystro
Polarity and the proximal causation for
cellular age asymmetry
A common theme emerging from the modeling exercises
is that for damage segregation to counteract clonal senescence, it has to be a spatially ordered processes giving rise
to distinct lineages within the population (Ackermann
et al., 2007; Nystrom, 2007, 2011; Erjavec et al., 2008;
Lindner et al., 2008). Experimental evidence supports this
notion of an ordered process as damage is predominantly
retained in the mother cells lineage of budding yeast
(Aguilaniu et al., 2003) and in old pole cells of E. coli
(Lindner et al., 2008; Winkler et al., 2010). Moreover,
damage segregation is under the control of several factors.
For example, asymmetrical inheritance of damage/aggregated proteins in yeast requires the protein disaggregase
Hsp104 (Erjavec et al., 2007; Tessarz et al., 2009), and this
spatial protein quality control (SQC) relies, in part, on the
deposition of misfolded proteins into specific protein
inclusions called IPOD and JUNQ (Spokoini et al., 2012).
Spatial partition of misfolded proteins into the JUNQ
(juxtanuclear inclusions) and IPOD (perivacuolar inclusions) compartments has been suggested to be part of a
cellular defense against proteotoxicity, and the destination
of the misfolded proteins depends on their ubiquitination
status and aggregation state – soluble ubiquitinated misfolded proteins accumulate in JUNQ where they may be
destroyed by the 26S proteasome, whereas terminally
aggregated proteins are sequestered in IPOD IBs (Kaganovich et al., 2008). Interestingly, this type of SQC occurs in
both yeast cells and mammalian cells (Kaganovich et al.,
2008). In yeast cells lacking Hsp104, IPOD/JUNQ inclusions of misfolded model proteins, such as the temperature-sensitive SUMO-conjugating enzyme Ubc9ts and the
Von Hippel–Lindau tumor suppressor protein (VHL), fail
to develop, and the smaller aggregates formed are increasingly inherited by the daughter cells (Spokoini et al.,
2012). However, it is clear that misfolded proteins that
form small aggregates rather than inclusions, such as the
Huntington’s disease proteins Htt103Q, are also asymmetrically inherited in an actin cable-dependent manner (Liu
et al., 2011), demonstrating that both inclusions and small
aggregates are subjected to spatial quality control. Besides
the protein remodeling factor Hsp104, protein deacetylases have been shown to be required for proper SQC;
HDAC6, in aggresome formation (Kawaguchi et al.,
2003), and the sirtuin, Sir2, a yeast gerontogene (Sinclair
& Guarente, 1997; Kaeberlein et al., 1999; Guarente,
2001), in the asymmetrical segregation of oxidized and
aggregated proteins (Aguilaniu et al., 2003; Erjavec et al.,
2007; Orlandi et al., 2010; Sampaio-Marques et al., 2012).
The polarisome machinery, which is required for actin
cable nucleation at the tip of the daughter cell (Dong
FEMS Yeast Res 14 (2014) 40–48
45
Protein quality control and aging
et al., 2003; Moseley & Goode, 2006), was identified in
two independent screens as an additional component
required for asymmetrical inheritance of damaged proteins in yeast (Tessarz et al., 2009; Liu et al., 2010), consistent with data showing that Sir2 is affecting actin
folding and functionality (Liu et al., 2011). In addition,
proper assembly of actin cables was demonstrated to be
required for deposition of misfolded proteins into peripheral inclusion bodies (Specht et al., 2011). Consistently,
3D imaging has shown that aggregates colocalize with
actin structures visualized with either the actin-binding
protein Abp140 or phalloidin (Liu et al., 2010, 2011).
Based on such results, it has been suggested that asymmetrical segregation of damaged proteins is a factordependent, genetically determined, process relying on a
functional actin cytoskeleton and the tethering of aggregates on organelle structures (Fig. 3; Aguilaniu et al.,
2003; Erjavec et al., 2007; Tessarz et al., 2009; Liu et al.,
2010, 2011; Spokoini et al., 2012).
This view contrasts with that of Zhou et al. (2011),
which, based on aggregate tracking experiments and modeling, argues that asymmetric inheritance is a predictable,
and purely passive, outcome of aggregates’ slow and random diffusion and the geometry of yeast cells. In this
view, aggregate inheritance is dictated solely by the diameter of the bud neck and how long this neck is opened
(generation time) for diffusion of aggregates (Fig. 3).
However, there is a large, and unexplained, amount of
diversity in the supposedly random movement of aggregates in the aggregate population recorded by Zhou et al.
(2011) such that many aggregates appear stationary in the
mother cell, while others move in a ballistic fashion.
Thus, the usefulness of employing an average diffusion
coefficient for this diverse population of aggregate
movements in attempting to draw conclusions about
inheritance being factor dependent or purely passive has
been questioned (Spokoini et al., 2012). It was shown by
Spokoini et al. (2012) that the larger aggregates in the
Zhou et al. (2011) study are IPOD and JUNQ inclusions
that cannot diffuse freely, or randomly, given that they
are tethered to the vacuole and nucleus, respectively.
The data suggesting that damage segregation is not
only dependent on, but also physically accomplished by,
the polarity machinery support the notion of a close link
between the evolution of polarity and lineage-specific
aging (Macara & Mili, 2008). A question of interest is
why a spatial, polar-dependent, inheritance of deleterious
material during cytokinesis is ‘favored’ over complete,
and temporal, damage removal. One possible answer to
this question is that some types of cytotoxic damage are
resistant to proteolytic attack. For example, carbonylation
is an irreversible oxidative modification, and carbonylated
proteins can form insoluble aggregates that appear to be
FEMS Yeast Res 14 (2014) 40–48
Factor-dependent retention
IPOD
Vacuole
Actin cables
Polarisome
Nucleus
Protein aggregates
JUNQ
Factor-independent random diffusion
Fig. 3. Two opposing models for the establishment of damage/
aggregate asymmetry during yeast cytokinesis. The upper picture
schematically depicts the factor-dependent model, suggesting that
asymmetrical segregation of damaged proteins is a factor-dependent
process relying on association/tethering of damaged proteins on
cellular structures, including the actin cytoskeleton and inclusion
bodies (IPOD and JUNQ) associated with the surface of the vacuole
and nucleus. The association between cytoskeletal and organelle
structures is, in this model, effectively preventing aggregated proteins
from diffusing freely into the daughter cell (Kaganovich et al., 2008;
Liu et al., 2010, 2011; Spokoini et al., 2012). The lower picture
depicts the random, factor-independent, diffusion model, which
states that asymmetry is a purely passive outcome of the aggregates’
slow, but random diffusion rate and the geometry of yeast cells. In
this view, aggregate inheritance is dictated solely by the diameter of
the bud neck and how long this neck is opened (generation time)
(Zhou et al., 2011).
difficult to degrade in both E. coli (Maisonneuve et al.,
2008) and yeast (Aguilaniu et al., 2003). In addition, the
complete removal of irreversibly damaged proteins may
come at a higher energetic (and fitness) cost compared
with damage segregation. Indeed, Macara & Mili (2008)
make the point that damage repair is never perfect, or
complete, and that the accumulation of damaged material
therefore is a universal problem of all cellular organisms.
As a consequence, it is suggested that polarity arose initially not to control morphogenesis, but as a solution to
the pivotal problem of inadequate damage repair and
clonal senescence (Macara & Mili, 2008).
Similar to yeast, E. coli apparently uses cues acting as
indicators of polarity to faithfully segregate protein
ª 2013 Federation of European Microbiological Societies.
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€m & B. Liu
T. Nystro
46
aggregates to the old cell pole of the aging cell lineages
(Lindner et al., 2008). However, in contrast to yeast, the
polar distribution of protein aggregates in E. coli is, to a
large extent, not the result of an active targeting, but
rather driven by nucleoid occlusion (Winkler et al.,
2010). Thus, cytosolic aggregation can be retargeted to
alternative, nonpolar, sites such as the inner membrane
when provided with ectopically generated, site-specific
aggregation seeds (Winkler et al., 2010). This raises the
question of how nucleoid occlusion of aggregates can
give rise to an ordered, pole-specific, segregation, an
interesting question to pursue.
Conclusion
In the face of inadequate damage repair, aging may have
evolved as the byproduct of a strong selection for polarity
and the division of labor between cells of unicellular
organisms (Ackermann et al., 2007; Erjavec et al., 2008;
Macara & Mili, 2008). The division of labor encompasses
an asymmetrical inheritance of potential aging factors, and
this has been argued to provide a conceptual microbial
analog to the germ cell/somatic cell demarcation (Guarente, 2010). Intriguingly, SQC and asymmetrical partitioning of damaged proteins are not unique for budding
yeast, but operate also in adult stem and progenitor cells
(Rujano et al., 2006). Specifically, using both epithelial
crypts of the small intestine of patients with a proteinfolding disease and Drosophila melanogaster neural precursor cells as models, Rujano et al. (2006) found that the
inheritance of protein aggregates during mitosis occurs
with a fixed polarity indicative of a mechanism aimed at
preserving the long-lived progeny. More recently, it was
demonstrated that oxidatively modified proteins are segregated asymmetrically during cytokinesis of neuroblast stem
cells (NB), the female germ line (GSC), and intestinal stem
cells (ISC) (Bufalino et al., 2013). Interestingly, the outcome of this segregation is different depending on the
stem cell type, while the ISC ‘rids itself’ of oxidatively
damaged proteins such that most of the damage is inherited by the progeny, cytokinesis of both GSC and NB
results in most of the damage being retained in the progenitor stem cell. The authors point out that the cell
receiving most damage in each case is, in fact, the one with
the shortest life span, and based on such results, the
authors propose a ‘life span asymmetry hypothesis’, stating
the damage inheritance determines progenitor–progeny
life span. Like for yeast cells, the authors conclude that this
is an active factor-dependent process (Bufalino et al.,
2013). At present, it is not known whether stem/progenitor cells utilize similar factors and machineries as budding
yeast to establish damage asymmetry – an interesting question worth pursuing. Likewise, elucidating mechanisms for
ª 2013 Federation of European Microbiological Societies.
Published by John Wiley & Sons Ltd. All rights reserved
spatial quality control may add to our understanding on
how aberrant/damaged proteins cause cytotoxicity and
whether spatial control can be targeted therapeutically to
mitigate proteotoxicity in neurological disorders.
Acknowledgements
Our work on spatial quality control is supported by
grants from the Swedish Natural Science Research Council (VR) (T.N. & B.L.), the Knut and Alice Wallenberg
Foundation (Wallenberg Scholar: T.N.), ERC (QualiAgeAdvanced Grant: T.N.), the Swedish Cancer Society
(CAN 2012/601: B.L.), and Stiftelsen Olle Engkvist
Byggm€astare Foundation (B.L.).
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