Septins are a family of GTP-binding proteins that associate with cellular membranes and the cytoskeleton. Their ability to polymerize into filamentous structures permits them to serve as diffusion barriers for membrane proteins and as multi-molecular scaffolds that recruit components of signaling pathways. At the cellular level, septins contribute to the regulation of numerous processes, including cytokinesis, cell polarity, cell migration, and many others. In this review, we discuss emerging evidence for roles of mammalian septins in the biogenesis and function of flagella and cilia, and how this may impact human diseases such as ciliopathies.
Septins are filamentous GTPases that play important but poorly characterized roles in ciliogenesis. Here, we show that SEPTIN9 regulates RhoA signaling at the base of cilia by binding and activating the RhoA guanine nucleotide exchange factor, ARHGEF18. GTP-RhoA is known to activate the membrane targeting exocyst complex, and suppression of SEPTIN9 causes disruption of ciliogenesis and mislocalization of an exocyst subunit, SEC8. Using basal body-targeted proteins, we show that upregulating RhoA signaling at the cilium can rescue ciliary defects and mislocalization of SEC8 caused by global SEPTIN9 depletion. Moreover, we demonstrate that the transition zone components, RPGRIP1L and TCTN2, fail to accumulate at the transition zone in cells lacking SEPTIN9 or depleted of the exocyst complex. Thus, SEPTIN9 regulates the recruitment of transition zone proteins on Golgi-derived vesicles by activating the exocyst via RhoA to allow the formation of primary cilia.
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