The evolution, complex structures and function of septin proteins

Abstract

The septin family is a conserved GTP-binding protein family and was originally discovered through genetic screening for budding yeast mutants. Septins are implicated in many cellular processes in fungi and metazoa. The function of septins usually depends on septin assembling into oligomeric complexes and highly ordered polymers. The expansion of the septin gene number in vertebrates increased the complex diversity of septins. In this review, we first discuss the evolution, structures and assembly of septin proteins in yeast and metazoa. Then, we review the function of septin proteins in cytokinesis, membrane remodeling and compartmentalization.

Fig. 1

X-ray structure of the human septin complex SEPT2–SEPT6–SEPT7. SEPT2–SEPT6–SEPT7 filament is arranged with alternating G-dimer interfaces and NC-dimer interfaces. Bound guanine nucleotide is also observed in the SEPT2–SEPT6–SEPT7 filament; both SEPT2 and SEPT7 are GDP-bound, while SEPT6 is GTP-bound. The NC-dimer interfaces and the G-dimer interfaces are indicated with black arrows and red arrows, respectively. The dashed arrows indicate the position and orientation of the coiled-coil domain. This figure is reproduced with the kind permission of the authors Sirajuddin et al. [38]

Fig. 2

Septin assembly in yeast and metazoa. a Septin assembly in yeast, Cdc42-dependent septin assembly. In yeast, assembly of the septin ring appears to have at least three steps: septin recruitment, septin ring assembly and septin ring maturation. Cdc42-GTP was required for the whole process of septin collar formation, which depends on activated Cdc42p and at least two partially redundant effector Gic1p and Gic2p. After septin recruitment, Cdc42, its GAPs (Rga1, Rga2 and Bem3), Cla4p, Gin4p, Elm1p, NAP1p and Bni1p are all required for septin ring assembly and maturation. Siz1p-related septin sumoylation is also involved in septin recruitment. b Metazoan septin assembly. Borg3, a CRIB motif containing protein and a Cdc42 effector, is required for metazoan septin assembly. Anillin, a conserved family of pleckstrin homology (PH)-domain proteins, is required for spatial control of metazoan septin organization. A Rho-guanine nucleotide exchange factor (GEF) SA-RhoGEF and a Rho effector Rhotekin are also involved in septin assembly. Whether the phosphorylation and/or sumoylation of septin could regulate septin assembly is still unknown

Fig. 3

Role of septins in mitotic exit and cytokinesis in yeast. In S. cerevisiae, Tem1p and Swe1p are involved in two important pathways regulating mitotic exit and cytokinesis separately. The activation of Tem1 by Lte1p leads to the activation of a kinase cascade, resulting in mitotic exit and cytokinesis. The Kin4ps provide additional layers of regulation by inhibition of the activation of Tem1p in the bud. This cell-cycle is also regulated by Swe1p protein kinase, which causes the inactivation of complexes of Cdc28p and mitotic cyclins. Several proteins were reported to function in septin regulating cytokinesis by controling Swe1p protein degradation. Protein kinases Gla4p and Cdc5p are located in the bud neck. If the septin collar is disturbed, Swe1p phosphorylation by Gla4p and Cdc5p were delayed and in turn promote the down-regulation of Swe1p. Another kinase Hsl1p could also promote Swe1p degradation and itself could be activated by relief of autoinhibition in response to septin interaction or phosphorylation promoted by the septin-associated kinase Elm1p. Septins may also function in the DNA replication checkpoint by interacting with Rad35, which could control the timely degradation of Swe1p during replication stress

Fig. 4

Role of septins in cell dividion in metazoa. Septins could function in cell division by several pathways. Septins could directly bind to CENP-E and stabilize the kinetochore and function in forming the correct tension at kinetochores of bi-orientated chromosomes. Septins bind directly to nonmuscle myosin II and are involved in the myosin II and the Rho-activated myosin kinases ROCK pathway. In addition, septins can reduce the stability of cellular microtubules (MTs) by binding to microtubule-associated protein 4 (MAP4). Septin rearrangement induced by DNA damages could induce rapid nuclear accumulation of NCK and SOCS7. All these pathways could function during cell cytokinesis