RRC ID 32802
Author Shi A, Liu O, Koenig S, Banerjee R, Chen CC, Eimer S, Grant BD.
Title RAB-10-GTPase-mediated regulation of endosomal phosphatidylinositol-4,5-bisphosphate.
Journal Proc Natl Acad Sci U S A
Abstract Caenorhabditis elegans RAB-10 and mammalian Rab10 are key regulators of endocytic recycling, especially in the basolateral recycling pathways of polarized epithelial cells. To understand better how RAB-10 contributes to recycling endosome function, we sought to identify RAB-10 effectors. One RAB-10-binding partner that we identified, CNT-1, is the only C. elegans homolog of the mammalian Arf6 GTPase-activating proteins ACAP1 and ACAP2. Arf6 is known to regulate endosome-to-plasma membrane transport, in part through activation of type I phophatidylinositol-4-phosphate 5 kinase. Here we show that CNT-1 binds to RAB-10 through its C-terminal ankyrin repeats and colocalizes with RAB-10 and ARF-6 on recycling endosomes in vivo. Furthermore, we find that RAB-10 is required for the recruitment of CNT-1 to endosomal membranes in the intestinal epithelium. Consistent with negative regulation of ARF-6 by RAB-10 and CNT-1, we found overaccumulation of endosomal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in cnt-1 and rab-10 mutants and reduced endosomal PI(4,5)P2 levels in arf-6 mutants. These mutants produced similar effects on endosomal recruitment of the PI(4,5)P2-dependent membrane-bending proteins RME-1/Ehd and SDPN-1/Syndapin/Pacsin and resulted in endosomal trapping of specific recycling cargo. Our studies identify a RAB-10-to-ARF-6 regulatory loop required to regulate endosomal PI(4,5)P2, a key phosphoinositide in membrane traffic.
Volume 109(35)
Pages E2306-15
Published 2012-8-28
DOI 10.1073/pnas.1205278109
PII 1205278109
PMID 22869721
PMC PMC3435156
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans / enzymology* Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Membrane / metabolism Clathrin / metabolism Endocytosis / physiology Endosomes / enzymology* GTP Phosphohydrolases / chemistry GTP Phosphohydrolases / metabolism* GTPase-Activating Proteins / chemistry GTPase-Activating Proteins / genetics GTPase-Activating Proteins / metabolism* Phosphatidylinositol 4,5-Diphosphate / metabolism* Protein Structure, Tertiary Protein Transport / physiology Two-Hybrid System Techniques rab GTP-Binding Proteins / chemistry rab GTP-Binding Proteins / metabolism*
IF 9.412
Times Cited 34
C.elegans tm2313 tm2526 tm1447