RRC ID 51381
Author Law F, Seo JH, Wang Z, DeLeon JL, Bolis Y, Brown A, Zong WX, Du G, Rocheleau CE.
Title The VPS34 PI3K negatively regulates RAB-5 during endosome maturation.
Journal J Cell Sci
Abstract The GTPase Rab5 and phosphatidylinositol-3 phosphate [PI(3)P] coordinately regulate endosome trafficking. Rab5 recruits Vps34, the class III phosphoinositide 3-kinase (PI3K), to generate PI(3)P and recruit PI(3)P-binding proteins. Loss of Rab5 and loss of Vps34 have opposite effects on endosome size, suggesting that our understanding of how Rab5 and PI(3)P cooperate is incomplete. Here, we report a novel regulatory loop whereby Caenorhabditis elegans VPS-34 inactivates RAB-5 via recruitment of the TBC-2 Rab GTPase-activating protein. We found that loss of VPS-34 caused a phenotype with large late endosomes, as with loss of TBC-2, and that Rab5 activity (mice have two Rab5 isoforms, Rab5a and Rab5b) is increased in Vps34-knockout mouse embryonic fibroblasts (Vps34 is also known as PIK3C3 in mammals). We found that VPS-34 is required for TBC-2 endosome localization and that the pleckstrin homology (PH) domain of TBC-2 bound PI(3)P. Deletion of the PH domain enhanced TBC-2 localization to endosomes in a VPS-34-dependent manner. Thus, PI(3)P binding of the PH domain might be permissive for another PI(3)P-regulated interaction that recruits TBC-2 to endosomes. Therefore, VPS-34 recruits TBC-2 to endosomes to inactivate RAB-5 to ensure the directionality of endosome maturation.
Volume 130(12)
Pages 2007-2017
Published 2017-6-15
DOI 10.1242/jcs.194746
PII jcs.194746
PMID 28455411
PMC PMC5482978
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans Caenorhabditis elegans Proteins / metabolism* Cell Membrane / metabolism Class III Phosphatidylinositol 3-Kinases / metabolism* Endosomes / metabolism* Fibroblasts / metabolism GTPase-Activating Proteins / metabolism* Green Fluorescent Proteins / metabolism Liposomes / chemistry Mice Mice, Knockout Mutation Phenotype Plasmids / metabolism Protein Domains RNA Interference rab5 GTP-Binding Proteins / metabolism*
IF 4.517
Times Cited 11
C.elegans tm2241