Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex | Zendy

Jennifer Hirst | Zendy; Geoffrey G. Hesketh | Zendy; AnneClaude Gingras | Zendy; Margaret S. Robinson | Zendy

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Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex

Author(s) -

Jennifer Hirst,

Geoffrey G. Hesketh,

AnneClaude Gingras,

Margaret S. Robinson

Publication year - 2021

Publication title -

the journal of cell biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.414

H-Index - 380

eISSN - 1540-8140

pISSN - 0021-9525

DOI - 10.1083/jcb.202002075

Subject(s) - endosome , phosphatidylinositol , gtpase , signal transducing adaptor protein , mtorc1 , microbiology and biotechnology , lysosome , phenotype , chemistry , biology , phosphorylation , signal transduction , biochemistry , pi3k/akt/mtor pathway , enzyme , gene , intracellular

Adaptor protein complex 5 (AP-5) and its partners, SPG11 and SPG15, are recruited onto late endosomes and lysosomes. Here we show that recruitment of AP-5/SPG11/SPG15 is enhanced in starved cells and occurs by coincidence detection, requiring both phosphatidylinositol 3-phosphate (PI3P) and Rag GTPases. PI3P binding is via the SPG15 FYVE domain, which, on its own, localizes to early endosomes. GDP-locked RagC promotes recruitment of AP-5/SPG11/SPG15, while GTP-locked RagA prevents its recruitment. Our results uncover an interplay between AP-5/SPG11/SPG15 and the mTORC1 pathway and help to explain the phenotype of AP-5/SPG11/SPG15 deficiency in patients, including the defect in autophagic lysosome reformation.

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