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 | ||||||||
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| 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 |
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| Divisions: | Division of Molecular Medicine | ||||||||
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| Depositing User: | Dr. sc. 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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