USP32-regulated LAMTOR1 ubiquitination impacts mTORC1 activation and autophagy induction

  • Highlights • USP32 deubiquitinates the Ragulator complex subunit LAMTOR1 at lysine (K) 20 • LAMTOR1 K20 ubiquitination impairs its binding to the vacuolar H+-ATPase • USP32 knockout reduces mTORC1 activity and elevates autophagic flux • Depletion of USP32 in Caenorhabditis elegans inhibits mTOR and induces autophagy Summary The endosomal-lysosomal system is a series of organelles in the endocytic pathway that executes trafficking and degradation of proteins and lipids and mediates the internalization of nutrients and growth factors to ensure cell survival, growth, and differentiation. Here, we reveal regulatory, non-proteolytic ubiquitin signals in this complex system that are controlled by the enigmatic deubiquitinase USP32. Knockout (KO) of USP32 in primary hTERT-RPE1 cells results among others in hyperubiquitination of the Ragulator complex subunit LAMTOR1. Accumulation of LAMTOR1 ubiquitination impairs its interaction with the vacuolar H+-ATPase, reduces Ragulator function, and ultimately limits mTORC1 recruitment. Consistently, in USP32 KO cells, less mTOR kinase localizes to lysosomes, mTORC1 activity is decreased, and autophagy is induced. Furthermore, we demonstrate that depletion of USP32 homolog CYK-3 in Caenorhabditis elegans results in mTOR inhibition and autophagy induction. In summary, we identify a control mechanism of the mTORC1 activation cascade at lysosomes via USP32-regulated LAMTOR1 ubiquitination.

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Author:Alexandra HertelORCiDGND, Ludovico Martins AlvesORCiD, Henrik Dutz, Georg TascherORCiDGND, Florian Bonn, Manuel KaulichORCiD, Ivan ĐikićORCiDGND, Stefan EimerGND, Florian SteinbergORCiDGND, Anja BremmORCiDGND
URN:urn:nbn:de:hebis:30:3-782825
DOI:https://doi.org/https://doi.org/10.1016/j.celrep.2022.111653
ISSN:2211-1247
Parent Title (English):Cell Reports
Publisher:Elsevier
Place of publication:Amsterdam
Document Type:Article
Language:English
Date of Publication (online):2022/12/06
Date of first Publication:2022/12/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/03/05
Tag:LAMTOR1; Rab7; Ragulator complex; USP32; autophagy; deubiquitinase (DUB); mTORC1; ubiquitin; v-ATPase
Volume:41
Issue:10, art. 111653
Article Number:111653
Page Number:26
HeBIS-PPN:520908538
Institutes:Medizin
Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International