Figure 9. Model of Rab35 function at the cilium.

1. Model of how activated (GTP‐bound) Rab35 at the ciliary and/or periciliary (pocket) membrane limits Arl13b ciliary levels. In one scenario, Rab35 inhibits Arl13b entry into cilia, possibly through an IFT pathway. In a second scenario, Rab35 promotes Arl13b exit/retrieval from ciliary (and periciliary) membranes via: (i) interaction with retrograde IFT, (ii) modulation of the transition zone membrane diffusion barriers that prevent Arl13b from exiting the cilum, and/or (iii) endocytic processes at or near the ciliary pocket that target Arl13b for degradation or recycling to non‐ciliary plasma membrane destinations.
2. Ciliary membrane and ciliary length phenotypes following Rab35 disruption. In wild‐type cells, Arl13b, INPP5E and Smoothened (SMO; under conditions of Shh signal activation) all localise to the ciliary membrane. Arl13b promotes the ciliary localisation of INPP5E 89, whilst limiting (or altering) the ciliary distribution of SMO 42. PI(4,5)P₂ (blue line) is enriched within the proximal portion of the ciliary membrane. In Rab35‐depleted cells, ciliary Arl13b levels are elevated, causing a concomitant increase and decrease in the ciliary levels of INPP5E and SMO, respectively. Rab35 disruption also leads to a reduction in the length of the proximal ciliary PI(4,5)P₂ signal and a reduction in the frequency of PI(4,5)P₂‐positive cilia (thin blue line). Misregulation of ciliary membrane protein composition in Rab35‐disrupted cells leads to a decrease in cilium length.