期刊
JOURNAL OF CELL SCIENCE
卷 130, 期 12, 页码 2007-2017出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.194746
关键词
Endosome; Rab GTPase; Phosphatidylinositide-3 phosphate; Vps34; TBC-2; Caenorhabditis elegans
类别
资金
- National Institutes of Health R01 grants [HL119478, GM97355]
- Canadian Institutes of Health Research operating grant [MOP-114935]
- Fonds de Recherche du Quebec - Sante
- Canada Foundation for Innovation
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-34dependent manner. Thus, PI(3) P binding of the PH domain might be permissive for another PI(3) P-regulated interaction that recruits TBC2 to endosomes. Therefore, VPS-34 recruits TBC-2 to endosomes to inactivate RAB-5 to ensure the directionality of endosome maturation.
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