Reactome | Cargo trafficking to the periciliary membrane

Cargo trafficking to the periciliary membrane

Stable Identifier

R-HSA-5620920

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Cargo trafficking to the periciliary membrane

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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
19081074	A BBSome subunit links ciliogenesis, microtubule stability, and acetylation Loktev, AV, Zhang, Q, Beck, JS, Searby, CC, Scheetz, TE, Bazan, JF, Slusarski, DC, Sheffield, VC, Jackson, PK, Nachury, MV	Dev. Cell	2008
20530210	The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis Li, Y, Wei, Q, Zhang, Y, Ling, K, Hu, J	J. Cell Biol.	2010
22085962	An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium Wright, KJ, Baye, LM, Olivier-Mason, A, Mukhopadhyay, S, Sang, L, Kwong, M, Wang, W, Pretorius, PR, Sheffield, VC, Sengupta, P, Slusarski, DC, Jackson, PK	Genes Dev.	2011
11384985	Flagellar protein dynamics in Chlamydomonas Song, L, Dentler, WL	J. Biol. Chem.	2001
22139371	Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes Zhang, Q, Nishimura, D, Seo, S, Vogel, T, Morgan, DA, Searby, C, Bugge, K, Stone, EM, Rahmouni, K, Sheffield, VC	Proc. Natl. Acad. Sci. U.S.A.	2011
20603001	The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia Jin, H, White, SR, Shida, T, Schulz, S, Aguiar, M, Gygi, SP, Bazan, JF, Nachury, MV	Cell	2010
12169685	A proteomic analysis of human cilia: identification of novel components Ostrowski, LE, Blackburn, K, Radde, KM, Moyer, MB, Schlatzer, DM, Moseley, A, Boucher, RC	Mol. Cell Proteomics	2002
23567335	Crosstalk of Arf and Rab GTPases en route to cilia Deretic, D	Small GTPases	2013
15314642	Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome Fan, Y, Esmail, MA, Ansley, SJ, Blacque, OE, Boroevich, K, Ross, AJ, Moore, SJ, Badano, JL, May-Simera, H, Compton, DS, Green, JS, Lewis, RA, van Haelst, MM, Parfrey, PS, Baillie, DL, Beales, PL, Katsanis, N, Davidson, WS, Leroux, MR	Nat. Genet.	2004
20145001	Molecular mechanisms of protein and lipid targeting to ciliary membranes Emmer, BT, Maric, D, Engman, DM	J. Cell. Sci.	2010
20038682	The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella Lechtreck, KF, Johnson, EC, Sakai, T, Cochran, D, Ballif, BA, Rush, J, Pazour, GJ, Ikebe, M, Witman, GB	J. Cell Biol.	2009
11684707	Intraflagellar transport balances continuous turnover of outer doublet microtubules: implications for flagellar length control Marshall, WF, Rosenbaum, JL	J. Cell Biol.	2001
23150559	ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting Humbert, MC, Weihbrecht, K, Searby, CC, Li, Y, Pope, RM, Sheffield, VC, Seo, S	Proc. Natl. Acad. Sci. U.S.A.	2012
17574030	A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis Nachury, MV, Loktev, AV, Zhang, Q, Westlake, CJ, Peränen, J, Merdes, A, Slusarski, DC, Scheller, RH, Bazan, JF, Sheffield, VC, Jackson, PK	Cell	2007
15998802	Proteomic analysis of a eukaryotic cilium Pazour, GJ, Agrin, N, Leszyk, J, Witman, GB	J. Cell Biol.	2005
22389062	The emerging role of Arf/Arl small GTPases in cilia and ciliopathies Li, Y, Ling, K, Hu, J	J. Cell. Biochem.	2012
20399632	The ciliary membrane Rohatgi, R, Snell, WJ	Curr. Opin. Cell Biol.	2010
9362062	Synthesis and turnover of embryonic sea urchin ciliary proteins during selective inhibition of tubulin synthesis and assembly Stephens, RE	Mol. Biol. Cell	1997
22326026	Proteomic analysis of mammalian primary cilia Ishikawa, H, Thompson, J, Yates, JR, Marshall, WF	Curr. Biol.	2012