The emerging functions of septins in metazoans

Abstract

Septins form a subfamily of highly related GTP-binding proteins conserved from eukaryotic protists to mammals. In most cases, septins function in close association with cell membranes and the actin and microtubule cytoskeleton to regulate a wide variety of key cellular processes. Further underscoring their importance, septin abnormalities are associated with several human diseases. Remarkably, septins have the ability to polymerize into assemblies of different sizes in vitro and in vivo. In cells, these structures act in the formation of diffusion barriers and scaffolds that maintain subcellular polarity. Here, we focus on the emerging roles of vertebrate septins in ciliogenesis, neurogenesis, tumorigenesis and host-pathogen interactions, and discuss whether unifying themes underlie the molecular function of septins in health and disease.

Figure 1

The septin ring paradigm. (A) Septins assemble at the neck of budding yeast cells in a ring-like collar. This functions as a diffusion barrier to control the exchange of molecules between the mother and the bud, and as a scaffold to anchor other proteins, such as astral microtubules emanating from the spindle pole body (centriole equivalent in yeast). Cilia contain a structurally and functionally analogous septin structure at their base. (B) In metazoans, membrane-associated septin assemblies are found at the base of the indicated cellular structures and around intracellular pathogens (Shigella flexneri). (C) Structure of the SEPT2 (turquoise)–SEPT6 (gold)–SEPT7 (dark grey) complex (Protein Data Bank: 2QAG; Sirajuddin et al, 2007). The proposed membrane-binding interface (polybasic region; Zhang et al, 1999) is shown in red and the arrows denote the NC- and G-oligomerization interfaces. When assembled into rings, these oligomers probably form filaments, but the orientation of filaments in metazoan septin rings is unknown. Images in panels B and C are reproduced with permission from the relevant publishers. SEPT, septin.

Figure 2

Possible roles for septins in cilia and neuronal synapses. (A) Septins might contribute to ciliogenesis in different ways. (1) The septin ring acts as a lateral diffusion barrier at the base of the cilium and controls the transport of membrane proteins. (2) The septin ring could provide the attachment site for the transition fibres (orange), directly or through adaptor proteins such as APC. (3) The septin ring might function as a scaffold to recruit and/or organize the function of the exocyst, PCP proteins and the BBSome. (4) Septins are also present at the tip and shaft of the cilium and could influence microtubule dynamics and the IFT. (5) Septins could also function in vesicle transport to the basal body. The red colour at the base of the cilium indicates the ciliary necklace region, which displays a high degree of positive membrane curvature, possibly recognized by amphipathic helices (such as in the BBSome subunit Arl6). (B) (1) Septins localize to the base of the dendritic spines, where they might act as lateral diffusion barriers to restrict exchange between the dendritic shaft and the spine. Septins could also influence spine morphogenesis by regulating (2) actomyosin structures or (3) microtubules. Moreover, (4) septins are enriched in the PSD and (5) hinder synaptic vesicle release at the presynaptic compartment by acting as membrane-apposed barriers. APC, adenomatous polyposis coli; BBSome, Bardet–Biedel syndrome proteins; IFT, intraflagellar transport; PCP, planar cell polarity; PSD, postsynaptic density.

Figure 3

Interplay between septins and the actin and microtubule cytoskeletons. (A) Septins localize to microtubules and might influence them in different ways: (1) guide microtubule growth and prevent their disassembly; (2) influence microtubule acetylation; (3) bind to polyglutamated microtubules; (4) act as scaffolds to recruit other proteins to microtubules; (5) regulate the motility of microtubule-driven motors such as CENP-E and influence vesicle transport along microtubules; and (6) interact with MAPs to control the dynamics and identity of microtubules. (B) In mammalian cells, some septins localize to actomyosin structures, including stress fibres, contractile rings and around actomyosin-covered intracellular bacteria. Septins are recruited to stress fibres by binding to NM2, and this interaction might be enhanced by different factors such as TNFα. Septins recruit ROCK and CRIK to promote MLC phosphorylation and actomyosin contractility, and can possibly recruit formins to promote actomyosin assembly. Images in panels A and B are reproduced with permission from the relevant publishers. CENP-E, centromere-associated protein E; CRIK, citron kinase; MAP, microtubule-associated protein; MLC, myosin light chain kinase; NM2, type II non-muscle myosin; TNFα, tumour necrosis factor α; ROCK, Rho kinase.