Microbiology (2016), 162, 1527–1534
Review
DOI 10.1099/mic.0.000359
Forging the ring: from fungal septins’ divergent
roles in morphology, septation and virulence to
factors contributing to their assembly into higher
order structures
Jose M. Vargas-Muñiz,1 Praveen R. Juvvadi2 and William J. Steinbach1,2
Correspondence
1
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham,
NC, USA
2
Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical
Center, Durham, NC, USA
William J. Steinbach
[email protected]
Septins are a conserved family of GTP-binding proteins that are distributed across different
lineages of the eukaryotes, with the exception of plants. Septins perform a myriad of functions in
fungal cells, ranging from controlling morphogenetic events to contributing to host tissue invasion
and virulence. One key attribute of the septins is their ability to assemble into heterooligomeric
complexes that organizse into higher order structures. In addition to the established role of
septins in the model budding yeast, Saccharomyces cerevisiae, their importance in other fungi
recently emerges. While newer roles for septins are being uncovered in these fungi, the
mechanism of how septins assemble into a complex and their regulation is only beginning to be
comprehended. In this review, we summarize recent findings on the role of septins in different
fungi and focus on how the septin complexes of different fungi are organized in vitro and in vivo.
Furthermore, we discuss on how phosphorylation/dephosphorylation can serve as an important
mechanism of septin complex assembly and regulation.
Introduction
Septins were discovered by Lee Hartwell when screening
for temperature-sensitive cell division mutants in the
model yeast Saccharomyces cerevisiae (Hartwell, 1971).
They are a conserved family of GTPases widely distributed
across major lineages of eukaryotes, with the exception of
plants (Nishihama et al., 2011; Pan et al., 2007). Septins
are characterized by four domains: the polybasic region,
the GTPase domain, the septin unique element and the
coiled-coil domain (Pan et al., 2007). The number of septin-encoding genes varies greatly between organisms,
ranging from 2 in the nematode Caenorhabditis elegans to
14 in humans (Hall et al., 2005; Nguyen et al., 2000). Sac.
cerevisiae and the pathogenic yeast Candida albicans
encode seven septins, including five mitotic septins (Cdc3,
Cdc10, Cdc11, Cdc12 and Sep7/Shs1) and two sporulation-specific septins (Spr3 and Spr28) (Hartwell, 1971;
Pan et al., 2007; Warenda & Konopka, 2002; Warenda
et al., 2003). In contrast, filamentous ascomycetes such as
Aspergillus spp., Neurospora crassa and Magnaporthe oryzae
Abbreviations: ER, endoplasmic reticulum; PP2A, protein phosphatase
2A.
000359 ã 2016 The Authors
contain four orthologues of Sac. cerevisiaecore septins and
one ancestral septin AspE (Berepiki & Read, 2013; Dagdas
et al., 2012; Juvvadi et al., 2011; Momany et al., 2001;
Pan et al., 2007; Vargas-Muñiz et al., 2015). The filamentous plant fungal pathogen, Fusarium graminearum, contains seven putative septin-encoding genes that include
the four core septins (Pan et al., 2007). The pathogenic
basidiomycetes, Cryptococcus neoformans and Ustilago
maydis, only express the core septins (Boyce et al., 2005;
Kozubowski & Heitman, 2010).
In addition to septins regulating cell division, they have
also been implicated in a myriad of cellular processes such
as cytoskeleton organization, vesicle trafficking, morphogenesis and cell wall maintenance (Table 1) (Chen et al.,
2016; Dagdas et al., 2012; Hernandez-Rodriguez et al.,
2012; Kozubowski & Heitman, 2010; Li et al., 2012b;
Lindsey et al., 2010a; Oh & Bi, 2011; Vargas-Muñiz et al.,
2015). In light of more recent literature emerging in the
field of fungal septins, here we review the divergent roles
of septins in the model and pathogenic fungi, with emphasis on their assembly into higher order structures and their
post-translation modification involving phosphorylation
and dephosphorylation.
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J. M. Vargas-Muñiz, P. R. Juvvadi and W. J. Steinbach
Table 1. Septins and their functions in model and pathogenic fungi
Organism
Hemiascomycetes
Sac. cerevisiae
Can. albicans
Ash. gossypii
Filamentous
ascomycetes
Asp. fumigatus
Asp. nidulans
N. crassa
M. oryzae
F. graminearum
Basidiomycetes
Cry. neoformans
U. maydis
Septins
Function
Reference
Cdc3, Cdc10,
Cdc11, Cdc12,
Shs1, Spr3,
Spr28
Cdc3, Cdc10,
Cdc11, Cdc12,
Shs1, Spr3,
Spr28
Cdc3, Cdc10,
Cdc11a,
Cdc11b,
Cdc12, Shs1,
Spr3, Spr28
AspA, AspB,
AspC, AspD,
AspE
AspA, AspB,
AspC, AspD,
AspE
Cdc3, Cdc10,
Cdc11, Cdc12,
Asp-1
Sep1, Sep3, Sep4,
Sep5, Sep6
FgCdc3,
FgCdc10,
FgCdc11,
FgCdc12
Cdc3, Cdc10,
Cdc11, Cdc12
Cell morphogenesis, chitin deposition,
spore cell wall formation, spore
membrane biogenesis, bud site
selection, cell cycle regulation
Hyphal growth, hyphal morphology, cell
wall stress, host tissue invasion
Hartwell (1971); Kim et al. (1991);
Fares et al. (1996); DeMarini et al.
(1997); Barral et al. (1999); Heasley &
McMurray (2016)
Warenda & Konopka (2002); Warenda
et al. (2003); Blankenship et al. (2010,
2014); Badrane et al. (2012)
Cell morphology, ascospore formation,
site of nuclear division
Helfer & Gladfelter (2006); Meseroll
et al. (2012); Meseroll et al. (2013)
Septation, conidiation, spore cell wall
organization, response to cell wall
stress
Negative regulation of new grow foci,
septation, conidiation, nuclei
distribution
Hyphal extension, septation, conidiation,
branching
Vargas-Muñiz et al. (2015)
Sep1, Sep2, Sep3,
Sep4
Septation, appressorium formation,
tissue invasion, virulence
Septation, conidiation, ascospore
formation, nuclear division, sexual
reproduction, stress response,
pathogenicity
Morphogenesis (sexual reproduction),
nuclei distribution, cell wall stress
response, virulence
Morphogenesis, filamentous growth,
teliospore formation
Septins in the maintenance of cell
morphology and cell wall dynamics
Fungal septins regulate cell morphology and the emergence
of new growth foci (Barral et al., 1999; Berepiki & Read,
2013; DeMarini et al., 1997; Hartwell, 1971; Helfer & Gladfelter, 2006; Hernandez-Rodriguez et al., 2012; Lindsey
et al., 2010a; Warenda & Konopka, 2002). In Can. albicans,
while the Cdc3 and Cdc12 septins are essential, the deletion
mutants of Cdc10 and Cdc11 septins could be obtained suggesting that the assembly of other septin complexes still
occurs in the absence of Cdc10 or Cdc11 reflecting their
roles in the morphogenetic events (Warenda & Konopka,
2002). In the filamentous ascomycetes, N. crassa and Asp.
nidulans, deletion of the core septins caused increased
branching (Berepiki & Read, 2013; Hernandez-Rodriguez
et al., 2012). Furthermore, heterologous expression of Asp.
nidulans AspC in Sac. cerevisiae induced aberrant pseudohyphal growth and provided supporting evidence for the role
of septins as key morphological regulators (Lindsey et al.,
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Lindsey et al. (2010a);HernandezRodriguez et al. (2012); HernandezRodriguez et al. (2014)
Berepiki & Read (2013)
Dagdas et al. (2012)
Chen et al. (2016)
Kozubowski & Heitman (2010)
Alvarez-Tabares & Perez-Martin (2010)
2010b). Despite the high level of homology between the
Asp. fumigatus and Asp. nidulans core septins, Asp. fumigatus septins are not involved in regulating new growth foci or
hyphal morphology (Vargas-Muñiz et al., 2015). It is possible that the Asp. fumigatus septin interactome and hyphal
morphology regulators were reprogrammed and their role
in morphology was lost during evolution. Septins from
basidiomycetes U. maydis and Cry. neoformans are involved
in cell morphology, further suggesting that this role is conserved and possibly lost in the Asp. fumigatus lineage
(Alvarez-Tabares & Perez-Martin, 2010; Boyce et al., 2005;
Kozubowski & Heitman, 2010).
Septins serve as micro-scale plasma membrane curvature
sensors in Ash. gossypii and possibly in other organisms
(Bridges et al., 2016). Ash. gossypii Cdc11a was found to
localize asymmetrically at the branching sites, with the most
highly curved side of the branch point enriched (Bridges
et al., 2016). Septins have a preference for positive curvature
(the base of branches), while in areas of negative curvature
(hyphal cell), septins localize parallel to the hyphal growth
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Functions and assembly of septins in fungi
axis. Purified Sac. cerevisiae septin complex mixed with supporter lipid bilayer coated beads showed that septins have a
preference for the 1 to 3 µm beads. This bead preference is
similar to the curvature observed in vivo. Septin interactants, such as Hsl7 in Ash. gossypii, can discriminate
between septins in the curved or straight surface, providing
a mechanism for the cell to recognize micro-scale curvature
(Bridges et al., 2016; Helfer & Gladfelter, 2006).
In addition to cell morphology, septins regulate cell wall
dynamics (Badrane et al., 2012; DeMarini et al., 1997; Kozubowski & Heitman, 2010; Vargas-Muñiz et al., 2015). Sac. cerevisiae septins localize chitin synthase activity via their
interaction with Bni4 during budding (DeMarini et al., 1997)
and Can. albicans septins are involved in chitin deposition
(Warenda & Konopka, 2002). In both Can. albicans and Asp.
fumigatus, septin localization is altered following exposure to
the b-glucan synthase inhibitor caspofungin. In addition,
deletion of the septin-encoding genes in Can. albicans, Asp.
fumigatus, U. maydis and Cry. neoformans increased their susceptibility to anti-cell wall agents (Alvarez-Tabares & PerezMartin, 2010; Badrane et al., 2012; Blankenship et al., 2014;
Kozubowski & Heitman, 2010; Vargas-Muñiz et al., 2015).
Although septins have an impact on the cell wall integrity
machinery, the precise mechanisms of their action remain
unclear in most fungi.
Septins control regularity of septation and
sporulation
In fungi, septins are well-known for their participation in
septation and spore production (Hartwell, 1971;
Hernandez-Rodriguez et al., 2012; Lindsey et al., 2010a;
Meseroll et al., 2012; Meseroll et al., 2013). In filamentous
ascomycetes, deletion of septin genes does not abolish septation but significantly reduces the number of septa in the
hyphae (Berepiki & Read, 2013; Chen et al., 2016; Dagdas
et al., 2012; Hernandez-Rodriguez et al., 2012; Lindsey
et al., 2010a; Vargas-Muñiz et al., 2015). In Sac. cerevisiae,
Ash. gossypii and F. graminearum, septins are involved in
ascospore formation (Chen et al., 2016; Fares et al., 1996;
Heasley & McMurray, 2016; Meseroll et al., 2013). Similarly, in N. crassa, Asp. nidulans, Asp. fumigatus and F. graminearum, septins play a critical role in the production of
conidia (Berepiki & Read, 2013; Chen et al., 2016;
Hernandez-Rodriguez et al., 2012; Lindsey et al., 2010a;
Vargas-Muñiz et al., 2015). While disorganization of conidiophores occurs in all the A. nidulans core septin deletion
strains, the conidiophores in Asp. fumigatus core septin
mutants resemble the WT strain (Hernandez-Rodriguez
et al., 2012; Lindsey et al., 2010a). It is important to note
that conidiophore morphology is highly divergent between
the two species. Although gene deletion does not impact the
morphology of conidiophores, the number of conidiophores in the Asp. fumigatus core septin deletion strains is
significantly lower than in the WT strain (unpublished
data). Not only do septins participate in conidiophore
development but they also regulate spore morphology in
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filamentous ascomycetes (Berepiki & Read, 2013; VargasMuñiz et al., 2015). In this context, the core septin deletion
strains produced spores that failed to separate properly
(Berepiki & Read, 2013; Vargas-Muñiz et al., 2015). Additionally, the spore cell wall organization was also abnormal
in the Asp. fumigatus mutants (Vargas-Muñiz et al., 2015).
Role of septins in the virulence of animal
and plant fungal pathogens
Septins have attracted attention due to their impact on the
virulence of both human and plant fungal pathogens.
(Alvarez-Tabares & Perez-Martin, 2010; Boyce et al., 2005;
Chen et al., 2016; Dagdas et al., 2012; Kozubowski & Heitman, 2010; Vargas-Muñiz et al., 2015; Warenda et al., 2003).
For example, in Can. albicans, the deletion of Cdc10 and
Cdc11 caused defects in invasive growth and attenuation of
virulence in a tail-vein injection model of candidiasis (Warenda et al., 2003). Similarly, in Cry. neoformans, the deletion
of septins attenuated virulence in the Galleria mellonella
insect model (Dagdas et al., 2012; Kozubowski & Heitman,
2010). However, in Asp. fumigatus, deletion of the septins
AspA, AspB and AspC resulted in hypervirulence in the G.
mellonella model of invasive aspergillosis but not deletions of
the others septins, AspD and AspE (Vargas-Muñiz et al.,
2015). Moreover, the DaspB strain showed increased TNF-a
production by bone marrow-derived macrophages (VargasMuñiz et al., 2015). Nonetheless, the hypervirulence phenotype was not recapitulated in an intranasal murine model of
invasive aspergillosis.
In the plant pathogen M. oryzae that causes rice blast disease, septin deletion strains were unable to cause infection
due to the disorganization of the F-actin network in the
appressorium (Dagdas et al., 2012; Kozubowski & Heitman,
2010). Also, in another plant pathogen, F. graminearum, the
deletion of core septins caused reduction in pathogenicity
(Chen et al., 2016). However, contribution of septins to virulence is not conserved among all plant pathogenic fungi.
In U. maydis, septins are dispensable for virulence but are
required for full symptom development (Alvarez-Tabares &
Perez-Martin, 2010; Boyce et al., 2005).
Septins act as scaffolds and diffusion
barriers
Participation of septins in different cellular processes is due
to their ability to act as scaffolds, recruiting other proteins
to specific cellular regions and acting as diffusion barriers
(Khan et al., 2015). In Sac. cerevisiae, septins at the bud
neck recruit a variety of proteins, including kinases and protein phosphatase 2A (PP2A) regulatory subunits, that have
cell cycle regulatory roles (Gladfelter et al., 2001; McMurray
& Thorner, 2009; Renz et al., 2016). These regulatory proteins associate with the septin complex at different stages of
the cell cycle, suggesting that a yet-unknown mechanism
can regulate septin–protein interaction (Bertin et al., 2008;
Khan et al., 2015; Renz et al., 2016). For example, septins
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J. M. Vargas-Muñiz, P. R. Juvvadi and W. J. Steinbach
recruit the kinase Gin4, which negatively regulates the flippase Fpk1 (Roelants et al., 2015). This results in the generation of asymmetry in the lipid bilayer, which could regulate
the distribution of lipids and proteins in the plasma
membrane.
Additionally, it has been proposed that septins act as diffusion barriers. In Sac. cerevisiae, the membrane protein Its2
and components of the polarisome complex are normally
found at the bud cells (Takizawa et al., 2000; TerBush et al.,
1996). When the Sac. cerevisiae septin mutant cdc12-6 is
grown at restrictive temperature, Its2 and the polarisome
complex are no longer restricted to the bud cells (Takizawa
et al., 2000). Recent studies implicate the possibility of septins acting as endoplasmic reticulum (ER) diffusion barriers
(Khan et al., 2015) for several possible reasons. First, Its2
primarily resides in the ER membranes (Wolf et al., 2012).
Second, Sec61, the ER membrane protein translocator, is
unable to move from the mother cell ER to the bud ER
(Bertin et al., 2012). Third, septin filaments are associated
with both plasma and ER membranes (Bertin et al., 2012).
Lastly, Epo1 and Scs2 (ER-associated proteins) interact with
septin Shs, and this interaction is integral for the compartmentalization of the ER membranes (Chao et al., 2014).
Nonetheless, the ER and plasma membrane diffusion barrier functions of septins are not necessarily mutually exclusive and more detailed investigation into these two possible
roles is required (Khan et al., 2015).
How do septins organize in higher order
structures?
Although the biological roles of septins have been explored
extensively, how they function and coordinate remains
unclear. One possible mechanism proposed is by the generation of asymmetries in fungal cells (Khan et al., 2015).
In order to generate asymmetries, septins assemble into
higher order structures. However, assembly of septins into
higher order structures, regulation of their assembly and
the role of post-translational modifications in the regulation of their assembly remain to be completely explored.
Regardless of the number or function of septins in the different organisms, one of the key shared attributes is their
ability to assemble into soluble heterooligomeric rodshaped complexes. These complexes usually contain two
copies of each septin (Bertin et al., 2008; Bridges et al.,
2014; Sirajuddin et al., 2007). Septins interact with each
other through two surfaces: one surface created by the Nterminus and the C-terminus of the globular GTPase
domain and the other one composed of the GTPase domain
(Sirajuddin et al., 2007). It is important to also note that
most septins do also have additional sequences at their Nterminus and C-terminus that are not part of the NC interface. The septin complexes in the form of rods are capable
of assembling from end to end to form filaments (Bertin
et al., 2008; Bridges et al., 2014; Meseroll et al., 2012; Sadian
et al., 2013). Although core septins are highly conserved in
1530
fungi, the composition of the heterooligomeric rods varies
between species.
Knowledge on septin assembly is mainly derived from an in
vitro model of Sac. cerevisiae in which the core septins are
organized into octameric rods in the following order: Cdc11Cdc12-Cdc3-Cdc10-Cdc10-Cdc3-Cdc12-Cdc11 (Fig. 1a)
(Bertin et al., 2008). Polymerization into filaments after dialysis is facilitated by end-to-end interaction of Cdc11. Septin
Shs1 is capable of replacing Cdc11 at the end of the octameric
rods; however, upon dialysis, the rods associate laterally
instead of end to end, forming a ring-like structure (Fig. 1b)
(Garcia et al., 2011). Although Ash. gossypii expresses the
same set of core septins as Sac. cerevisiae, Ash. gossypii septins
form a heteromeric complex that contains all five septin subunits (Cdc10, Cdc11, Cdc3, Cdc12 and Shs1) (Fig. 1c) (Meseroll et al., 2012).
Septin organization in other fungi has not been explored in
as much detail as in the hemiascomycetes. Through genetic
deletion and proteomic analyses, it has been suggested that
the core septins in the filamentous ascomycetes N. crassa,
Asp. nidulans and Asp. fumigatus follow pattern of organization similar to that of the core septins in Sac. cerevisiae
(Fig. 1d) (Berepiki & Read, 2013; Hernandez-Rodriguez
et al., 2012, 2014; Vargas-Muñiz et al., 2015). In addition to
the core septins, filamentous ascomycetes also express a
non-core septin (N. crassa: Asp-1; Asp. nidulans and Asp.
fumigatus: AspE) (Berepiki & Read, 2013; HernandezRodriguez et al., 2014; Juvvadi et al., 2013; Vargas-Muñiz
et al., 2015). Immunoprecipitation of the non-core septin
also yields the entire septin complex during the multicellular growth stage, suggesting that Asp-1/AspE interacts with
the core septins (Berepiki & Read, 2013; Hernandez-Rodriguez et al., 2014; Juvvadi et al., 2013) However, when core
septins are used for the immunoprecipitation, Asp-1/AspE
is relatively lower in abundance compared to the core septins (Berepiki & Read, 2013; Hernandez-Rodriguez et al.,
2014; Vargas-Muñiz et al., 2015). Interestingly, Asp. nidulans AspE only seems to interact with the septin complex
during multicellular growth, while the core septins interact
with each other during isotropic, unicellular polar and multicellular growth (Hernandez-Rodriguez et al., 2014). Thus,
Asp-1/AspE associates with the septin complex but is not
an integral component of such a complex. Additionally,
AspE seems to be interacting with AspB during the multicellular growth stage (Fig. 1e) (Hernandez-Rodriguez et al.,
2014).
Although knowledge on how septins polymerize and organize
into higher order structures in vitro is available, their assembly
in vivo is less well understood. With the use of fluorescence
correlation spectroscopy in Sac. cerevisiae, Ash. gossypii and
Schizosaccharomyces pombe, it was determined that septins
exist as heteromeric rods containing one or two copies of each
septin in the cytoplasm (Bridges et al., 2014). In the plasma
membranes of Sch. pombe and Ash. gossypii, septins are capable of diffusing in two dimensions as discrete spots and filaments. Then, septins’ rods in the plasma membrane can
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Microbiology 162
Functions and assembly of septins in fungi
Saccharomyces cerevisiae
(a)
(b)
Ashbya gossypii
(c)
Aspergillus nidulans
(d)
(e)
?
Cdc11/AspA
Cdc12/AspC
Cdc3/AspB
Cdc10/AspD
Shs1
AspE
?
Fig. 1. Schematic of septin heterooligomeric complexes in fungi. Fungal septin associates with each other to form rods that contain two copies of each associated septin. (a and b) Sac. cerevisiae heterooligomeric rods. (a) Cdc11 is replaced by (b) Shs1 at
the end of the rods. While Cdc11 can associate with other rods via Cdc11, Shs1 associates laterally with other rods’ Shs1 forming a ring-like, higher order structure. (c) Ash. gossypii septin heterooligomeric complex contains two copies of each mitotic septin. (d) Asp. nidulans core septins associate with each other during each of the developmental growth stages. (e) AspE
associates with the core septin complex during multicellular stage of growth, through a presumptive interaction with AspB.
associate by the end forming short filaments through a process called annealing (Bridges et al., 2014).
Septins also require other interacting partners to form
higher order structures. For instance, Cdc42, cycling
between GTP- and GDP-bound form and its GAP are
required for proper septin ring organization in Sac. cerevisiae (Caviston et al., 2003; Gladfelter et al., 2002). Additionally, the Cdc42 effectors, Gic1 and Gic2, have a role in
septin ring organization (Iwase et al., 2006). In vitro analyses with purified Sac. cerevisiae septins and Gic1 showed
that Gic1 interacts with the septin filaments to form a railroad-like structure (Sadian et al., 2013). Furthermore, electron microscopy showed that Gic1 directly interacts with
septin Cdc10 and a reconstituted septin complex without
Cdc10. Gic1 and Cdc42-GDP compete for the same Cdc10binding site; however, Gic1 has a stronger affinity. Gic1
interacts with Cdc42-GTP and the increased concentration
of Cdcd42-GTP destabilizes the septin–Gic1-Cdc42 complex, resulting in the loss of railroad-like structures (Sadian
et al., 2013).
2002; Tang & Reed, 2002; Versele & Thorner, 2004). Cdc3
is phosphorylated at S9, S503 and S509 (Chi et al., 2007;
Tang & Reed, 2002), and mutation of these serines into alanines resulted in delayed budding and impaired the disassembly of old septin rings (Tang & Reed, 2002). Cdc10 is
phosphorylated at S256 and S312, and mutation of S256 to
alanine resulted in elongated buds at 37 C (Versele &
Thorner, 2004). The non-core septin Shs1 is also highly
phosphorylated compared to the core septins in Sac. cerevisiae. In vitro dialysis analysis using a phosphomimetic Shs1
revealed the importance of phosphorylation in regulating
septin higher order structure assembly (Garcia et al., 2011).
What is the role of phosphorylation in
regulating septins?
The Can. albicans Cdc11 and Shs1/Sep7 septins are also
known to be phosphorylated (Gonzalez-Novo et al., 2008;
Li et al., 2012a; Sinha et al., 2007). Cdc11 is phosphorylated
in a growth-dependent manner. In the yeast form of Can.
albicans, Cdc11 is phosphorylated at S4 and S395 (Sinha
et al., 2007). Upon hyphal induction, Cdc11 is phosphorylated at S4, S394 and S395. Phosphorylation of S394 and
S395 is crucial for the maintenance of polarized growth in
Can. albicans hyphae (Sinha et al., 2007). Although phosphorylation of S394 and S395 is important for hyphal morphology, phosphorylation of these sites is not required for
proper Cdc11 localization.
Septin phosphorylation has been explored extensively, and
a majority of the core septins Cdc3, Cdc11, Cdc10 and Shs1
are phosphorylated in Sac. cerevisiae (Chi et al., 2007; Dobbelaere et al., 2003; Ficarro et al., 2002; Mortensen et al.,
In the filamentous hemiascomycete Ash. gossypii, Cdc11,
Cdc12, Cdc2 and Shs1 are also phosphorylated in vivo
(Meseroll et al., 2013). Phosphorylation site mutations in
Cdc11 (S314A) and Cdc3 (S91D) resulted in aberrant spore
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morphology, and mutated septins failed to localize to any
structure. Phosphomimetics of all Shs1 sites (Shs1 9D) is
recessive lethal. Shs1 9A has decreased mobility and Shs1
9D shows increase dynamics in interregion rings as measured by FRAP (Meseroll et al., 2013). Thus, ring dynamics
could be regulated through phosphorylation of Shs1.
In the filamentous ascomycetes, phosphorylation of septins
has been so far examined only in Asp. fumigatus. The septins
AspB and AspE were shown to be phosphorylated in vivo
during the multicellular stage of growth (Juvvadi et al., 2013;
Vargas-Muñiz et al., 2016). The core septin AspB is phosphorylated in seven residues, five of these phosphorylation
sites are in the GTPase domain and two are in the C-terminus
(Vargas-Muñiz et al., 2016). AspE is phosphorylated in six
residues: one in the N-terminus, four in the GTPase domain
and one after the septin unique element in the C-terminus
(Juvvadi et al., 2013). Considering the fact that hemiascomycete septins showed little or no phosphorylation within their
GTPase domains, the specific biological functions of these
phosphorylation sites need to be addressed in future.
Kinases and phosphatases in the
regulation of septins
In hemiascomycetes, the cyclin-dependent kinase Cdc28, the
PAK family kinase Cla4 and the Nim1-related kinase Gin4 are
known to regulate septin ring dynamics through phosphorylation (DeMay et al., 2009; Kadota et al., 2004; Li et al., 2012a;
Longtine et al., 1998; Sinha et al., 2007; Versele & Thorner,
2004; Wightman et al., 2004). In Sac. cerevisiae, Cdc28 regulates Shs1 and Cdc3 phosphorylation in a cell cycle-dependant
manner (Asano et al., 2006; Tang & Reed, 2002). Can. albicans
Cdc28 phosphorylates Cdc11 after hyphal induction, and this
phosphorylation is required for hyphal formation (Sinha
et al., 2007). Additionally, phosphorylation of Cdc11 by
Cdc28 could be primed by previous phosphorylation of
Cdc11 by Gin4 (Sinha et al., 2007). Phosphorylation of Cdc3
by Cdc28 plays a role in septin ring disassembly, and Cdc3
might be phosphorylated at late G1 (Tang & Reed, 2002). In
addition to direct regulation of septins, Cdc28 indirectly regulates septin phosphorylation by phosphorylating Gin4 (Asano
et al., 2006; Li et al., 2012a; Mortensen et al., 2002). Sac. cerevisiae Gin4 co-purifies with the septin complex during mitosis,
where Gin4 phosphorylates Shs1 (Mortensen et al., 2002).
Similarly, in Can. albicans, the timing of Sep7 disassociation
from the bud neck is regulated by Gin4-dependent phosphorylation (Li et al., 2012a). Additionally, Can. albicans Gin4 septin-binding domain and lipid-binding domain can promote
septin higher order assembly in a Gin4-phosphorylation-independent mechanism (Au Yong et al., 2016). In Ash. gossypii
and Asp. fumigatus, Gin4 is required for proper localization of
septins (DeMay et al., 2009; Vargas-Muñiz et al., 2016). However, Asp. fumigatus Gin4 seems to regulate septin localization
through a septin-phosphorylation-independent mechanism
yet to be fully explored (Vargas-Muñiz et al., 2016). Interestingly, in Sch. pombe, the Gin4 orthologue (Cdr2) acts independently of septins (Morrell et al., 2004). Septins are also
1532
regulated by the p21-associated kinase Cla4 in Sac. cerevisiae
(Cvrekova et al., 1995; Versele & Thorner, 2004). Cla4 phosphorylates the core septins Cdc3 and Cdc10 in vitro (Versele
& Thorner, 2004). Furthermore, Cla4 phosphorylation of
Cdc10 serine 256 is important for the maintenance of proper
yeast morphology at 37 C (Versele & Thorner, 2004). Similar
to Gin4, Cla4 is required for proper localization of Asp. fumigatus AspB in a septin-phosphorylation-independent fashion
(Vargas-Muñiz et al., 2016).
Although the role of kinases in septin higher order assembly
has been explored, even less is known on the role of phosphatases in regulating septin dynamics and assembly. In
Sac. cerevisiae, the PP2A complex plays a key role when septin rings become more dynamic during telophase (Dobbelaere et al., 2003). This correlates with the PP2A regulatory
subunit Rts1 translocation from the kinetochore to the bud
neck. Furthermore, Shs1 is dephosphorylated in an Rts1dependent manner (Dobbelaere et al., 2003). Similarly in
Can. albicans, the PP2A subunit Tpd3 has been implicated
in the dephosphorylation of Sep7 (Shs1 homologue) in vivo
(Liu et al., 2016). In Asp. fumigatus, AspB is dephosphorylated in a ParA-dependent (the Rts1 homologue) manner
(Vargas-Muñiz et al., 2016). Asp. fumigatus AspB is phosphorylated in seven residues, and in the absence of ParA,
two additional sites were identified (T68 and S447). While
alanine or glutamic acid mutation of the phosphosites
altered AspB localization, only the substitution of T68 to
glutamic acid resulted in increased apical compartment
length. These multiple lines of evidence point to the key
role of the PP2A family in dephosphorylating septins in
fungal cells. Further exploration of phosphorylation/
dephosphorylation mechanisms involved in septin regulation is required in other fungal species.
Conclusion
Septins have a fundamental role in cytokinesis and their
importance in other aspects of fungal growth, morphology
and virulence is recently emerging. In order to carry out
their function, septins assemble into higher order structures. These structure dynamics are regulated by phosphorylation/dephosphorylation through direct or indirect action
of kinases and phosphatases. Recent studies have shed light
on how septins can act as scaffolds; however, the mechanisms that allow septins to carry out their full function
remain to be completely elucidated. Future targeted proteomic analyses could provide an insight into septin-interacting partners and how these interactions facilitate septins
functions in the fungal cells.
Acknowledgements
J. M. V.-M. was supported by National Science Foundation Graduate
Research Fellowship Programme DGF 1106401. P. R. J. and W. J. S. are
supported in part by 1 R01 AI112595-01. Any opinion, findings and
conclusions expressed in this publication are those of the authors and
do not necessarily reflect the views of the National Science Foundation.
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Functions and assembly of septins in fungi
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