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

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 GTPa...

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Autores principales: Hirst, Jennifer, Hesketh, Geoffrey G., Gingras, Anne-Claude, Robinson, Margaret S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814351/
https://www.ncbi.nlm.nih.gov/pubmed/33464297
http://dx.doi.org/10.1083/jcb.202002075
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author Hirst, Jennifer
Hesketh, Geoffrey G.
Gingras, Anne-Claude
Robinson, Margaret S.
author_facet Hirst, Jennifer
Hesketh, Geoffrey G.
Gingras, Anne-Claude
Robinson, Margaret S.
author_sort Hirst, Jennifer
collection PubMed
description 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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spelling pubmed-78143512021-01-29 Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex Hirst, Jennifer Hesketh, Geoffrey G. Gingras, Anne-Claude Robinson, Margaret S. J Cell Biol Article 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. Rockefeller University Press 2021-01-19 /pmc/articles/PMC7814351/ /pubmed/33464297 http://dx.doi.org/10.1083/jcb.202002075 Text en © 2021 Hirst et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hirst, Jennifer
Hesketh, Geoffrey G.
Gingras, Anne-Claude
Robinson, Margaret S.
Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex
title Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex
title_full Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex
title_fullStr Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex
title_full_unstemmed Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex
title_short Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex
title_sort rag gtpases and phosphatidylinositol 3-phosphate mediate recruitment of the ap-5/spg11/spg15 complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814351/
https://www.ncbi.nlm.nih.gov/pubmed/33464297
http://dx.doi.org/10.1083/jcb.202002075
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