TY  - JOUR
A1  - Hertel, Alexandra
A1  - Alves, Ludovico Martins
A1  - Dutz, Henrik
A1  - Tascher, Georg
A1  - Bonn, Florian
A1  - Kaulich, Manuel
A1  - Đikić, Ivan
A1  - Eimer, Stefan
A1  - Steinberg, Florian
A1  - Bremm, Anja
T1  - USP32-regulated LAMTOR1 ubiquitination impacts mTORC1 activation and autophagy induction
T2  - Cell Reports
N2  - 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.
KW  - ubiquitin
KW  - deubiquitinase (DUB)
KW  - USP32
KW  - Rab7
KW  - LAMTOR1
KW  - Ragulator complex
KW  - v-ATPase
KW  - mTORC1
KW  - autophagy
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/78282
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-782825
SN  - 2211-1247
VL  - 41
IS  - 10, art. 111653
PB  - Elsevier
CY  - Amsterdam
ER  -