GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways
| Autor: | Silva Hećimović, Cecilia Bucci, Rom Paz, Kristina Dominko, Hagit Eldar-Finkelman, Limor Avrahami |
|---|---|
| Přispěvatelé: | Avrahami, Limor, Paz, Rom, Dominko, Kristina, Hecimovic, Silva, Bucci, Cecilia, Eldar-Finkelman, Hagit |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Endosome media_common.quotation_subject Endocytic cycle mTORC1 macromolecular substances Mechanistic Target of Rapamycin Complex 1 Acidification 03 medical and health sciences Glycogen Synthase Kinase 3 Mice 0302 clinical medicine Rab5 GSK-3 Tuberous Sclerosis Lysosome Rab7 medicine Autophagy Animals Internalization Biology Late endosome media_common rab5 GTP-Binding Proteins TSC Endocytosi Chemistry rab7 GTP-Binding Proteins Basic Medical Sciences Cell Biology L803-mt GSK-3 inhibitor Endocytosis Cell biology Protein Transport 030104 developmental biology medicine.anatomical_structure rab GTP-Binding Proteins 030220 oncology & carcinogenesis mTOR lysosomes acidification autophagy endocytosis L803-mts GSK-3 inhibitors Lysosomes Acids Signal Transduction |
| Zdroj: | Cellular signalling |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|