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GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways

Avrahami, Limor; Paz, Rom; Dominko, Kristina; Hećimović, Silva; Bucci, Cecilia; Eldar-Finkelman, Hagit (2020) GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways. Cellular signalling, 71 . ISSN 0898-6568

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Abstract

Impaired lysosomal activity, which results in defective protein processing, waste accumulation, and protein aggregation, is implicated in a number of disease pathologies. Acidification of lysosomes is a crucial process required for lysosome function. Previously we showed that inhibition of glycogen synthase kinase-3 (GSK-3) enhanced lysosomal acidification in both normal and pathological conditions. However, how GSK-3 integrates into the lysosome networking is unknown. Here we show that inhibition of mTORC1 and increased autophagic activity are downstream to GSK-3 inhibition and contribute to lysosomal acidification. Strikingly, lysosomal acidification is also restored by GSK-3 inhibition in the absence of functional autophagy, and, independently of mTORC1. This is facilitated by increased endocytic traffic: We show that GSK-3 inhibition enhanced material internalization, increased recruitment of active Rab5 into endosomes, and increased Rab7/RILP clustering into lysosomes, all processes required for late endosome maturation. Consistently, in cells defective in endocytic traffic caused by either constitutively active Rab5, or, deletion of the Niemann-Pick C1 protein, GSK-3 inhibition could not restore lysosomal acidification. Finally we found that the tuberous sclerosis complex, TSC, is required for lysosomal acidification and is activated by GSK-3 inhibition. Thus, the GSK-3/TSC axis regulates lysosomal acidification via both the autophagic and endocytic pathways. Our study provides new insights into the therapeutic potential of GSK-3 inhibitors in treating pathological conditions associated with impaired cellular clearance.

Item Type: Article
Uncontrolled Keywords: GSK-3 ; Lysosomes ; Acidification ; Autophagy ; Endocytosis ; Rab5 ; Rab7 ; mTOR ; TSC ; L803-mts ; GSK-3 inhibitors
Subjects: NATURAL SCIENCES > Biology
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions: Division of Molecular Medicine
Projects:
Project titleProject leaderProject codeProject type
Molekularni mehanizam neurodegeneracije u Niemann-Pickovoj bolesti tip CKatušić Hećimović, SilvaIP-2016-06-2799HRZZ
Depositing User: Silva Katušić Hećimović
Date Deposited: 15 Feb 2022 12:50
URI: http://fulir.irb.hr/id/eprint/6999
DOI: 10.1016/j.cellsig.2020.109597

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