The VPS-34 PI3 kinase negatively regulates RAB-5 during endosome maturation
| Autor: | Yousstina Bolis, Fiona Law, Jennifer L. DeLeon, Jung Hwa Seo, Guangwei Du, Ashley Brown, Wei-Xing Zong, Ziqing Wang, Christian E. Rocheleau |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Endosome Green Fluorescent Proteins Endosomes GTPase Animals Genetically Modified Mice 03 medical and health sciences 0302 clinical medicine Protein Domains Pi Animals Caenorhabditis elegans Caenorhabditis elegans Proteins PI3K/AKT/mTOR pathway rab5 GTP-Binding Proteins Mice Knockout biology Cell Membrane GTPase-Activating Proteins fungi Cell Biology Fibroblasts biology.organism_classification Class III Phosphatidylinositol 3-Kinases Cell biology Pleckstrin homology domain Endosome localization Phenotype 030104 developmental biology Liposomes Mutation RNA Interference Rab 030217 neurology & neurosurgery Plasmids Research Article |
| Zdroj: | Journal of Cell Science. |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.194746 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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