Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Septin

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101986

Synonyms

 SEPT1: Septin 1; DIFF6; LARP; PNUTL3; SEP1

 SEPT2: Septin 2; DIFF6; NEDD-5; NEDD5; Pnutl3; hNedd5; KIAA0158

 SEPT3: Septin 3; SEP3; bK250D10.3

 SEPT4: Septin 4; H5; ARTS; MART; SEP4; CE5B3; PNUTL2; hucep-7; BRADEION; hCDCREL-2

 SEPT5: Septin 5; H5; CDCREL; PNUTL1; CDCREL1; CDCREL-1; HCDCREL-1

 SEPT6: Septin 6; KIAA0128; MGC16619; MGC20339; SEP2

 SEPT7: Septin 7; CDC3; CDC10; SEPT7A

 SEPT8: Septin 8; KIAA0202; SEP2

 SEPT9: Septin 9; MSF; MSF1; NAPB; SINT1; PNUTL4; SeptD1; AF17q25; KIAA0991; Ov/Br septin

 SEPT10: Septin 10; FLJ11619; sept1-like

 SEPT11: Septin 11; FLJ10849

 SEPT12: Septin 12; FLJ25410; SPGF10

 SEPT14: Septin 14; FLJ44060

Historical Background

Septins were initially identified in the budding yeast, Saccharomyces cerevisiae, as genes essential for cytoplasmic division (Hartwell 1971; Hartwell et al. 1970). While the isolation and characterization of yeast mutants with defects in cell-cycle control yielded a Nobel Prize for Leland Hartwell, septin mutants which displayed a “multinucleated hyphae” phenotype was one of his less popular discoveries. The name “septin” was assigned to indicate its role in the formation of septum, a structure which separates mother and bud during yeast cell division (Byers and Goetsch 1976; Sanders and Field 1994). Most of the initial understanding and the name “septin” originated in the John Pringle lab between the 1970s and 1990s (Pringle 2008). In the initial decades, septin research was restricted to yeasts and filamentous fungi, but septin family genes were later identified in all eukaryotes excluding higher plants. General interest on mammalian septin research was ignited by the isolation of septin gene translocations and fusions in leukemia, but a direct role for septins in tumorigenesis has not been established yet (reviewed in (Cerveira et al. 2011)). Consistent with its role in septation in the fungi, septins are mainly involved in the process of cytokinesis in higher eukaryotes (Neufeld and Rubin 1994). Initially, septin dependence of cytokinesis was considered to be obligate in animals and fungi, but septin mutant animal models have suggested the existence of septin-independent cytokinesis (Menon and Gaestel 2015; Menon et al. 2014). In addition, studies in the past decade have led to the identification of several noncanonical functions of the septin family proteins, establishing septins as the fourth component of the mammalian cytoskeleton (reviewed in (Mostowy and Cossart 2012)).

Structure, Classification, and Polymerization

Septins are ubiquitously expressed multidomain proteins with a central conserved GTP-binding and hydrolyzing domain (G-domain) flanked by more variable N-terminal and C-terminal regions. Other conserved elements include an N-terminal polybasic region that interacts with lipids and a C-terminal “septin-unique element” (Fig. 1a). The number of septin genes varies among different organisms with 7 in S. cerevisiae, 2 in C. elegans, 5 in D. melanogaster, and 13 in mice and humans. The different septin family proteins differ in their N- and C-terminal regions, harboring proline-rich domains and coiled-coil regions, respectively. Septin heteropolymers are formed via alternating N–C and G–G domain interfaces (Sirajuddin et al. 2007, 2009). While most septins strongly bind GTP and slowly hydrolyze it, it is not clear whether GTP-hydrolysis is obligatory for septin function (Sirajuddin et al. 2009; Abbey et al. 2016). Interestingly, many temperature-sensitive septin mutations in yeast are concentrated in and around conserved G-domain residues (Weems et al. 2014).
Septin, Fig. 1

Structure and assembly of septins. (a) General domain organization of septins depicted with indicated proline-rich domain (PRD), polybasic region (PBR), GTP-binding domain, septin-unique element (SUE), and coiled-coil region (CC). (b) Canonical hetero-oligomeric complexes (hexamer/octamer) of septins formed by alternate N–C and G–G interfaces. (c) Schematic representation of possible higher order assembly by septins

Based on the similarities in their sequences, the 13 mammalian septins are classified into four homology based groups: SEPT2 group (SEPT1, 2, 4, & 5), SEPT3 group (SEPT3, 9, & 12), SEPT6 group (SEPT6, 8, 10, 11, & 14), and SEPT7 group (SEPT7) (Kinoshita 2003; Versele and Thorner 2005; Weirich et al. 2008). Earlier studies in yeast already showed that septins decorate filamentous structures at the mother-bud junction during budding. In vitro polymerization studies further established the filament-forming nature of septins (Versele et al. 2004). Septin family proteins form nonpolar heteropolymers with flexible subunit composition, albeit with some extent of subunit order and specificity (Frazier et al. 1998; Versele et al. 2004; McMurray et al. 2011). The most well studied minimal repeating units of septins consist of a hexamer “SEPT7:6:2:2:6:7” or an octamer “SEPT9:7:6:2:2:6:7:9” (Fig. 1b), wherein the individual proteins could be substituted by other members of the same group (Sirajuddin et al. 2009; Kim et al. 2011). This leads to a significant amount of functional redundancy within the septin family. In addition, the presence of several splice variants of each septin gene leads to a wide variety of possible septin heteropolymers in diverse tissues and organs. This capability to form an array of higher-order assemblies including filaments, bundles, cages, and rings with diverse subunit composition adds to the uniqueness of septin cytoskeleton (Fig. 1c). SEPT7, being the only member of the SEPT7 group, cannot be substituted and thus forms a pivotal member of the septin family. Notably, depletion of SEPT7 causes codepletion of all the core subunits of the basic octamer, leading to a general septin deficiency (Sellin et al. 2011; Menon et al. 2014). Consistent with these observations, mouse knockouts of different septin genes display phenotypes ranging from subtle defects to early embryonic lethality (Table 1).
Septin, Table 1

Phenotypes associated with septin deficiency in knockout models

Septin

Group

Expression

Mouse knockout phenotype

SEPT1

SEPT2

Lymphocytes, CNS

Unavailable

SEPT2

SEPT2

Ubiquitous

Unavailable

SEPT3

SEPT3

CNS

No abnormalities in the CNS (Fujishima et al. 2007)

SEPT4

SEPT2

Lymphocytes, CNS, platelets, testes, etc.

↑Liver fibrosis (Iwaisako et al. 2008); mitochondrial fission defects, male sterility, etc. (Ihara et al. 2005; Kissel et al. 2005)

SEPT5

SEPT2

Ubiquitous

↑Platelet sensitivity (Dent et al. 2002), cognitive functions (Peng et al. 2002; Suzuki et al. 2009)

SEPT6

SEPT6

Ubiquitous

No detectable abnormalities, no effect on MLL-Sept6-induced leukemia model (Ono et al. 2005)

SEPT7

SEPT7

Ubiquitous

Embryonic lethality, KO MEFs multinucleated (Kinoshita 2008; Menon et al. 2014); defective neuronal morphogenesis (Ageta-Ishihara et al. 2013); normal development but context-dependent activation defects in T-lymphocytes (Menon et al. 2014; Mujal et al. 2015)

SEPT8

SEPT6

CNS, heart, platelets, lymphocytes, etc.

No developmental defects, pathological myelin out-foldings leading to decelerated nerve conduction (Patzig et al. 2016)

SEPT9

SEPT3

Ubiquitous

Embryonic lethality, conditional KO MEFs survive with migration/cell morphology defects (Fuchtbauer et al. 2011)

SEPT10

SEPT6

Ubiquitous

Preweaning lethality – with incomplete penetrance (Brown and Moore 2012)

SEPT11

SEPT6

Ubiquitous

Embryonic lethality (Roseler et al. 2011)

SEPT12

SEPT3

Lymphocytes, testes

Defective spermiogenesis in chimeric mice (Lin et al. 2009)

SEPT14

SEPT6

CNS, testes

Unavailable

Septins in Animal Cell Cytokinesis

The discovery of the Drosophila septin homolog denoted as “peanut” due to the cellular morphology associated with defective cytokinesis in the mutant fly was the first instance hinting towards the mechanistic similarity between yeast budding and animal cell cytokinesis (Neufeld and Rubin 1994). Evolutionarily conserved and expected role for septin proteins in cytokinesis was confirmed soon after the discovery of the mammalian septin genes (Kinoshita et al. 1997; Surka et al. 2002; Nagata et al. 2003). siRNA-mediated depletion of septin isoforms were shown to result in proliferation and cytokinesis defects in diverse cell line models, but the role played by septins in cytokinesis seems to be pleiotropic and cell/context specific. Septins associate with the spindle microtubules and regulate chromosomal segregation in HeLa and MDCK cells (Spiliotis et al. 2005). Studies in Drosophila and Caenorhabditis models have established roles for septins in bridging the acto-myosin contractile ring to the cytoplasmic membrane, generating ring asymmetry, curvature, and contraction (Maddox et al. 2007; Guillot and Lecuit 2013; Mavrakis et al. 2014). Septin isoform-specific roles were also proposed in mammalian cells wherein depletion of SEPT9 leads to late-stage cytokinetic defects, while SEPT7/SEPT2/SEPT11 depletion affects early stages of cytoplasmic division (Estey et al. 2010).

Early indication for septin-independent cytokinesis in animals arose from the fact that septin mutant flies and worms underwent normal early embryonic development. Recent studies in Drosophila neuro-epithelium could clearly show coexistence of septin-dependent and independent epithelial cytokinesis depending on the plane of cell-division with respect to the epithelial layer (Founounou et al. 2013). While most of the mammalian epithelial cells studied in culture were susceptible to septin depletion, early studies could show septin-independent survival and proliferation of some blood-derived cell lines. More importantly, the generation of the conditional Sept7-deficient mouse established the fact that the in vivo development of hematopoietic lineages could follow septin-independent routes for cytokinesis (Menon et al. 2014). However, a context-dependent role for septins in lymphocyte activation and proliferation was later established, which reconfirms the complexity of the process (Mujal et al. 2015). The viability of inhibiting septin-dependent cytokinesis to fight solid tumors, without the usual myelo-suppressive effect of current chemotherapeutic strategies needs further discussion and experimentation (reviewed in (Menon and Gaestel 2015)).

Noncanonical Functions of Septins

One of the major functions of the septin ring at the yeast bud-neck is to act as a diffusion barrier preventing free diffusion of membrane-proteins and organelles from mother to the bud, by closely associating with the membranes. This membrane proximal function of septin cytoskeleton is retained in mammals, and septins strongly bind to micron-scale cytoplasmic membrane curvatures (Bridges et al. 2016). A septin ring associated selective diffusion barrier at the dendritic spine necks or the base of a primary cilium and thus regulates neuronal morphogenesis and ciliogenesis, respectively (Tada et al. 2007; Hu et al. 2010; Ewers et al. 2014). A similar septin-ring function is also critical for sperm-tail maturation and function (Ihara et al. 2005; Kissel et al. 2005). The submembrane septin network is also thought to play roles in stabilizing the cell cortex, modulating cell shape changes, and migration (Tooley et al. 2009; Kim et al. 2010; Fuchtbauer et al. 2011; Gilden et al. 2012; Shindo and Wallingford 2014).

Septins also associate with the SNARE proteins and are involved in vesicular transport (reviewed in (Song et al. 2016)). Platelets express many septin genes, and platelet degranulation was found to be deregulated in the Sept5 KO model (Dent et al. 2002; Röseler et al. 2005). Septins are also thought to be necessary for the formation of phagosomes (Huang et al. 2008). Many invasive and intracellular bacterial pathogens induce septin rearrangements in host cells for gaining entry into nonphagocytic cells (reviewed in (Torraca and Mostowy 2016)). Interestingly, cage-like septin structures entrap intracellular Shigella and deliver them to autophagosomes for degradation, limiting bacterial spread and infection (Mostowy et al. 2010). Recent studies have hinted towards a role for mitochondria in septin-cage formation, providing evidence for septin function in mitochondrial fission and morphogenesis (Pagliuso et al. 2016; Sirianni et al. 2016). In the context of infection and pathogenesis, septins are also responsible for the extraordinary half-life of Botulinum neurotoxin light chain-A within target cells enhancing neuroparalytic effect of the toxin strain (Vagin et al. 2014).

Septins are crucial for cell proliferation and for this simple reason have always been of interest in the cancer field. Moreover, the identification of several MLL-septin fusion genes in leukemia generated greater interest in the potential role of septins in oncogenesis (Cerveira et al. 2011). Large numbers of septin mutations as well as expression changes of septin genes have been identified in cancer cells, but a causative relation to tumorigenesis has not been made yet (Liu et al. 2010; Angelis and Spiliotis 2016). SEPT9 gene was found to be strongly methylated in colorectal cancer (CRC) tissues and is considered as a biomarker for early detection of CRC, by simple testing in the blood for tumor-derived methylated DNA (Warren et al. 2011; Yoruker et al. 2016). Interestingly, a recent study clearly demonstrated a role for septins in the development of protumorigenic cancer-associated fibroblasts (Calvo et al. 2015). In addition, the general role of septins in the regulation of growth factor receptors, mitochondrial fission, and cell polarity could have implications in tumorigenesis (reviewed in (Pous et al. 2016)).

Mammalian Septins: Posttranslational Modifications and Signaling

Septins are highly dynamic and complex polymers. Their weakly conserved terminal domains exposed at the filament surface are thought to interact with a diverse array of proteins, making them most suitable signaling hubs. In yeast, septins associate with a large number of kinases, regulating distinct phases of cell cycle progression (reviewed in (Perez et al. 2016)). While mammalian SEPT1, SEPT2, SEPT3, and SEPT5 are phosphorylated by kinases including AURKB, casein kinase 2, PKC, PKA, PKG, and CDK5, the precise signaling mechanism and functional consequences are not well established (Xue et al. 2000, 2004; She et al. 2004; Qi et al. 2005; Taniguchi et al. 2007; Yu et al. 2009). CDK5-mediated phosphorylation of SEPT5 was found to regulate syntaxin binding and thus regulate exocytosis (Taniguchi et al. 2007). A signaling complex consisting of ERK3, MAPKAPK-5 (MK5), and SEPT7 was found to regulate septin-dependent dendritic branching in hippocampal neurons and SEPT8 was found to be a direct substrate of MK5 (Brand et al. 2012; Shiryaev et al. 2012). Septins interact with the cdc42-effector proteins of the BORG family and could thus crosstalk with actin-dependent mechanotransduction (Joberty et al. 2001; Calvo et al. 2015). Recruitment of ERK3/MK5 to SEPT7 is thought to facilitate BORG phosphorylation by these kinases (Brand et al. 2012). Mutagenesis analysis of a potential phospho-tyrosine residue in SEPT7 (Y318) showed that this site may regulate the specificity of septin-septin interactions, but neither the in vivo relevance nor the phosphorylating kinase has been investigated so far (Sandrock et al. 2011). Enteropathogenic E. coli (EPEC) and Shigella infection were recently shown to induce SEPT9 N-terminal phosphorylation which was found to be necessary for the adhesion of EPEC to host cells (Scholz et al. 2015). Interestingly, another N-terminal phosphorylation site on SEPT9 was shown to be important for the completion of cytokinesis. In this case, CDK1 was identified as the responsible kinase and the mechanism involved the phosphorylation-dependent binding of the peptidyl-prolyl cis-trans isomerase PIN1 to SEPT9 (Estey et al. 2013). These findings are more important if one considers the fact that SEPT9 occupies the terminal position in the septin heteromer assembly and seems to have several N-terminally truncated splice forms (Estey et al. 2010; Kim et al. 2011).

Yeast septins have been shown to undergo a wide array of modifications in addition to phosphorylation (reviewed in (Hernandez-Rodriguez and Momany 2012)), but there is less information available regarding posttranslational modifications of the mammalian family members. SEPT5 levels were upregulated in the Parkin KO mice brain and parkin could ubiquitinate SEPT5 in vitro (Choi et al. 2003; Periquet et al. 2005). RNF8, another evolutionarily conserved ubiquitin ligase involved in DNA-damage signaling and mitotic arrest was shown to ubiquitinate SEPT7 (Chahwan et al. 2013). SUMOylation of SEPT2 was found to be necessary for chromosome congression during meiosis (Zhu et al. 2010).

In addition to being a target of signaling pathways, septins can have indirect and direct role as signaling platforms and adaptor proteins. For example, SEPT9 was shown to negatively regulate ubiquitin-dependent EGFR degradation (Diesenberg et al. 2015), and SEPT7 was shown to recruit HDAC6 to promote tubulin deacetylation (Ageta-Ishihara 2013). One of the most significant findings regarding a possible “septin signalosome” has been the discovery of septin function in calcium signaling and store-operated calcium entry (SOCE) (Sharma et al. 2013). Septins play a complex role in calcium signaling, which seems to vary depending on the cell-type, septin composition, and the calcium store (Deb et al. 2016) (reviewed in (Deb and Hasan 2016)). Unraveling this complexity will be a key to understand the mechanisms behind the noncanonical functions of septins in immune cells and the brain.

Summary

Septins constitute a family of filament forming p-loop GTPases, with evolutionarily conserved role in cytoplasmic division from yeast to mammals. The 13 mammalian septins (SEPT1–12 and SEPT14) are classified into 4 groups based on sequence homology, and they undergo heteropolymerization into repeating hexameric or octameric units which assemble into higher-order structures including rings and cages. While septin cytoskeleton seems to be indispensable for embryogenesis and fibroblast proliferation, the development of blood lineages seems to follow septin-independent cytokinesis. In addition to their role in cytokinesis, different septin family proteins also participate in neuronal morphogenesis, spermiogenesis, ciliogenesis, and vesicular transport. Septins directly associate with cytoplasmic membranes and form a submembrane cortical network regulating cell morphology, polarity, and migration. In addition to being signaling scaffolds, they act as important mediators of host-pathogen interactions during bacterial infections. Recent reports also could show a role for septins in the regulation of store-operated calcium entry. Understanding the basis of the cell-type specificity of septin function in cytokinesis and calcium signaling will reveal opportunities for therapeutic septin targeting in inflammation and cancer.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Cell BiochemistryHannover Medical School (MHH)HannoverGermany