Reactome: A Curated Pathway Database

Cargo trafficking to the periciliary membrane

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

Proteomic studies suggest that the cilium is home to approximately a thousand proteins, and has a unique protein and lipid make up relative to the bulk cytoplasm and plasma membrane (Pazour et al, 2005; Ishikawa et al, 2012; Ostrowoski et al, 2002; reviewed in Emmer et al, 2010; Rohatgi and Snell, 2010). In addition, the cilium is a dynamic structure, and the axoneme is continually being remodeled by addition and removal of tubulin at the distal tip (Marshall and Rosenbaum, 2001; Stephens, 1997; Song et al, 2001). As a result, the function and structure of this organelle relies on the directed trafficking of protein and vesicles to the cilium. Small GTPases of the RAS, RAB, ARF and ARL families are involved in cytoskeletal organization and membrane traffic and are required to regulate the traffic from the Golgi and the trans-Golgi network to the cilium (reviewed in Deretic, 2013; Li et al, 2012). ARF4 is a Golgi-resident GTPase that acts in conjunction with a ciliary-targeting complex consisting of the ARF-GAP ASAP1, RAB11A, the RAB11 effector FIP3 and the RAB8A guanine nucleotide exchange factor RAB3IP/RABIN8 to target cargo bearing a putative C-terminal VxPx targeting motif to the cilium. A well-studied example of this system involves the trafficking of rhodopsin to the retinal rod photoreceptors, a specialized form of the cilium (reviewed in Deretic, 2013). ARL3, ARL13B and ARL6 are all small ARF-like GTPases with assorted roles in ciliary trafficking and maintenance. Studies in C. elegans suggest that ARL3 and ARL13B have opposing roles in maintaining the stability of the anterograde IFT trains in the cilium (Li et al, 2010). In addition, both ARL3 and ARL13B have roles in facilitating the traffic of subsets of ciliary cargo to the cilium. Myristoylated cargo such as peripheral membrane protein Nephrocystin-3 (NPHP3) is targeted to the cilium in a UNC119- and ARL3-dependent manner, while ARL13B is required for the PDE6-dependent ciliary localization of INPP5E (Wright et al, 2011; Humbert et al, 2012; reviewed in Li et al, 2012). ARL6 was also identified as BBS3, a gene that when mutated gives rise to the ciliopathy Bardet-Biedl syndrome (BBS). ARL6 acts upstream of a complex of 8 other BBS-associated proteins known as the BBSome. ARL6 and the BBSome are required for the ciliary targeting of proteins including the melanin concentrating hormone receptor (MCHR) and the somatostatin receptor (SSTR3), among others (Nachury et al, 2007; Loktev et al, 2008; Jin et al, 2010; Zhang et al, 2011). Both the BBSome and ARL6 may continue to be associated with cargo inside the cilium, as they are observed to undergo typical IFT movements along the axoneme (Fan et al, 2004; Lechtreck et al, 2009; reviewed in Li et al, 2012).

Literature References
PubMed ID Title Journal Year
9362062 Synthesis and turnover of embryonic sea urchin ciliary proteins during selective inhibition of tubulin synthesis and assembly Mol. Biol. Cell 1997
22326026 Proteomic analysis of mammalian primary cilia Curr. Biol. 2012
20399632 The ciliary membrane Curr. Opin. Cell Biol. 2010
22389062 The emerging role of Arf/Arl small GTPases in cilia and ciliopathies J. Cell. Biochem. 2012
15998802 Proteomic analysis of a eukaryotic cilium J. Cell Biol. 2005
17574030 A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis Cell 2007
23150559 ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting Proc. Natl. Acad. Sci. U.S.A. 2012
11684707 Intraflagellar transport balances continuous turnover of outer doublet microtubules: implications for flagellar length control J. Cell Biol. 2001
20038682 The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella J. Cell Biol. 2009
20145001 Molecular mechanisms of protein and lipid targeting to ciliary membranes J. Cell. Sci. 2010
15314642 Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome Nat. Genet. 2004
23567335 Crosstalk of Arf and Rab GTPases en route to cilia Small GTPases 2013
12169685 A proteomic analysis of human cilia: identification of novel components Mol. Cell Proteomics 2002
20603001 The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia Cell 2010
22139371 Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes Proc. Natl. Acad. Sci. U.S.A. 2011
11384985 Flagellar protein dynamics in Chlamydomonas J. Biol. Chem. 2001
22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium Genes Dev. 2011
20530210 The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis J. Cell Biol. 2010
19081074 A BBSome subunit links ciliogenesis, microtubule stability, and acetylation Dev. Cell 2008
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Orthologous Events