Rab GTPases in cilium formation and function

Abstract

Cilia are microtubule-based organelles extending from a basal body at the surface of eukaryotic cells. Cilia regulate cell and fluid motility, sensation and developmental signaling, and ciliary defects cause human diseases (ciliopathies) affecting the formation and function of many tissues and organs. Over the past decade, various Rab and Rab-like membrane trafficking proteins have been shown to regulate cilia-related processes such as basal body maturation, ciliary axoneme extension, intraflagellar transport and ciliary signaling. In this review, we provide a comprehensive overview of Rab protein ciliary associations, drawing on findings from multiple model systems, including mammalian cell culture, mice, zebrafish, C. elegans, trypanosomes, and green algae. We also discuss several emerging mechanistic themes related to ciliary Rab cascades and functional redundancy.

Rab35 controls cilium length, function and membrane composition

“…Third, depletion of a Rab35 GAP (TBC10D1A) elongates cilia, whereas depletion of a Rab35 GEF (DENND1B) truncates cilia. Thus, Rab35 joins a number of other Rabs, namely Rab8, Rab11 and Rab23 (reviewed in [32]) required for normal cilium structure. In the context of cilium length regulation, it is interesting that the truncated RAB35-deficient cilia exhibit increased ARL13B levels, given reports of abnormally long cilia in cells overexpressing Arl13b [44,97].…”

“…G protein activity is tightly regulated, with guanine nucleotide exchange factors (GEFs) promoting GTP binding, and GTPase-activating proteins (GAPs) enhancing the G protein's intrinsic GTPase activity which, when present, hydrolyses GTP to GDP [29]. Currently, at least nine of the 66 Rabs that comprise this family of GTPases (Rab 5/8/10/11/17/23/28/29/34), as well as 3 Rab-like proteins (Rabl2/ 4/5), are linked to cilium formation and/or function, and the control of ciliary membrane protein levels [30][31][32][33][34]. For example, vertebrate and mammalian Rab11-Rabin8-Rab8 cascades are involved in early steps of cilium formation, and rhodopsin transport to the photoreceptor cell cilium (outer segment) [35][36][37].…”

Binding of IFT22 to the intraflagellar transport complex is essential for flagellum assembly

“…IFT22 lacks the conventional G4 motif and contains a highly diverse G5 motif required for interaction with the guanine base of GTP/GDP (Rensland et al, 1995;Vetter & Wittinghofer, 2001;Itzen & Goody, 2011). Mutation of the Caenorhabditis elegans (Ce) IFT22 homolog (called IFTA-2) does not affect cilium formation or IFT, but worms show deficiencies in the DAF-2 (insulin-IGF-1-like) signaling pathway, leading to an extended lifespan and abnormalities in dauer stage formation (Schafer et al, 2006;Blacque et al, 2018). Interestingly, in vivo studies in several ciliated organisms revealed functional differences of IFT22 between species.…”

Endosome maturation factors Rabenosyn‐5/VPS45 and caveolin‐1 regulate ciliary membrane and polycystin‐2 homeostasis

“…Finally, it is interesting to note that membrane trafficking genes such as RAB‐5 and those related to clathrin‐mediated endocytosis are largely dispensable for ciliogenesis whilst still participating in ciliary protein trafficking (reviewed in Blacque et al , ). Indeed, further analysis of two mutants from our original screen, cav‐1 and wdfy‐2 , confirms non‐essential roles for these genes in defining cilium formation and morphology (Fig EV5C), yet both are required for ciliary PKD‐2 homeostatic control ( cav‐1 ) and/or PKD‐2‐associated male mating behaviours ( cav‐1 , wdfy‐2 ).…”