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Comment
. 2013 Apr-Jun;4(2):106-9.
doi: 10.4161/sgtp.23477. Epub 2013 Feb 7.

Interactions between Rab and Arf GTPases regulate endosomal phosphatidylinositol-4,5-bisphosphate during endocytic recycling

Anbing Shi  1 , Barth D Grant
Affiliations
Comment

Interactions between Rab and Arf GTPases regulate endosomal phosphatidylinositol-4,5-bisphosphate during endocytic recycling

Anbing Shi et al. Small GTPases. 2013 Apr-Jun.

Abstract

After endocytosis, a selective endocytic recycling process returns many endocytosed molecules back to the plasma membrane. The RAB-10/Rab10 GTPase is known to be a key recycling regulator for specific cargo molecules. New evidence, focused on C. elegans RAB-10 in polarized epithelia, points to a key role of RAB-10 in the regulation of endosomal phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) levels. In turn, PI(4,5)P2 levels strongly influence the recruitment of many peripheral membrane proteins, including those important for vesicle budding through their membrane bending activities. Part of the effect of RAB-10 on endosomal PI(4,5)P2 is through its newly identified effector CNT-1, a predicted GTPase activating protein (GAP) of the small GTPase ARF-6/Arf6. In mammals PI(4,5)P2 generating enzymes are known Arf6 effectors. In C. elegans we found that RAB-10, CNT-1 and ARF-6 are present on the same endosomes, that RAB-10 recruits CNT-1 to endosomes, and that loss of CNT-1 or RAB-10 leads to overaccumulation of endosomal PI(4,5)P2, presumably via hyperactivation of endosomal ARF-6. In turn this leads to over-recruitment of PI(4,5)P2-dependent membrane-bending proteins RME-1/Ehd and SDPN-1/Syndapin/PACSIN. Conversely, in arf-6 mutants, endosomal PI(4,5)P2 levels were reduced and endosomal recruitment of RME-1 and SDPN-1 failed. This work makes an unexpected link between distinct classes of small GTPases that control endocytic recycling, and provides insight into how this interaction affects endosome function at the level of lipid phosphorylation.

Keywords: ACAP; ARF-6; Arf6; C. elegans; CNT-1; GAP; RAB GTPase; RAB-10; Rab10; Rab35; clathrin; endocytic recycling; phosphatidylinositol-4,5-bisphosphate.

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Figures

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Figure 1. Coordinate Rab/Arf GTPase cascades influence multiple cellular processes. (A) In C. elegans, RAB-10 and ARF-6 act in sequential steps via CNT-1/Arf GAP to regulate endosomal PI(4,5)P2 levels and membrane recruitment of recycling traffic related PI(4,5)P2-binding proteins RME-1 and SDPN-1. (B) In mammalian systems, Rab35(GTP) recruits ACAP2/Arf GAP and thus regulates Arf6 activity. Rab35-mediated regulation of Arf6 via ACAP2 is important for NGF-induced outgrowth of neurite and phagocytosis. Recent studies suggested that Arf6 can recruit MICAL-L1 onto endosomes and regulate EHD1 and Rab8 localization/function indirectly. Arf6(GTP) also interacts with the Rab35 GAP EPI64B, negatively regulating Rab35 activity. This Arf6-to-Rab35 cascade is necessary for endocytic trafficking during cytokinesis.
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