The ins and outs of the Arf4-based ciliary membrane-targeting complex

The small GTPase Arf4-based ciliary membrane-targeting complex recognizes specific targeting signals within sensory receptors and regulates their directed movement to primary cilia. Activated Arf4 directly binds the VxPx ciliary-targeting signal (CTS) of the light-sensing receptor rhodopsin. Recent findings revealed that at the trans-Golgi, marked by the small GTPase Rab6, activated Arf4 forms a functional complex with rhodopsin and the Arf guanine nucleotide exchange factor (GEF) GBF1, providing positive feedback that drives further Arf4 activation in ciliary trafficking. Arf4 function is conserved across diverse cell types; however, it appears that not all its aspects are conserved across species, as mouse Arf4 is a natural mutant in the conserved α3 helix, which is essential for its interaction with rhodopsin. Generally, activated Arf4 regulates the assembly of the targeting nexus containing the Arf GAP ASAP1 and the Rab11a-FIP3-Rabin8 dual effector complex, which controls the assembly of the highly conserved Rab11a-Rabin8-Rab8 ciliary-targeting module. It was recently found that this module interacts with the R-SNARE VAMP7, likely in its activated, c-Src-phosphorylated form. Rab11 and Rab8 bind VAMP7 regulatory longin domain (LD), whereas Rabin8 interacts with the SNARE domain, capturing VAMP7 for delivery to the ciliary base and subsequent pairing with the cognate SNAREs syntaxin 3 and SNAP-25. This review will focus on the implications of these novel findings that further illuminate the role of well-ordered Arf and Rab interaction networks in targeting of sensory receptors to primary cilia. Abbreviations: CTS: Ciliary-Targeting Signal; GAP: GTPase Activating Protein; GEF: Guanine Nucleotide Exchange Factor; RTC(s), Rhodopsin Transport Carrier(s); SNARE: Soluble N-ethylmaleimide-sensitive Factor Attachment Protein Receptor; TGN: Trans-Golgi Network.