GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways
Authors: Silva Hecimovic
Hagit Eldar-Finkelman
Kristina Dominko
Rom Paz
Limor Avrahami
Cecilia Bucci
Journal: Cellular Signalling (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Acidification; Autophagy; Endocytosis; GSK-3; GSK-3 inhibitors
Affiliations: The Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel., Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia., Department of Biological and Environmental Sciences and Technologies (DiSTeBA), Università del Salento, Via Provinciale Lecce-Monteroni Lecce, Italy., The Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: .

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. 

Retracted: No

PubPeer comments:
 ![file] Figure 5. A These images are of identical cultures but at different zoom. The NT panels. If yes, the scale becomes irrelevant too! Any explanations authors? , 
 A panel in Figure 3B and Figure 7C seem very similar, yet are described differently. Could the authors please check? Apologies if I m misunderstanding something. *** ![file] , 
 1. I agree, this is a mistake where NT photo is the same, we apologize for this and will be happy to fix it. 2. These are MEF cells, where WT=TSC1 2++, in Fig 3B we compared WT with PS1- - cells, and in Fig 7C we compared the same WT (written as TSC1 2++) with TSC- - cells. The important point is of course the changes seen in the KO cells (PS- - and TSC- - right panel ). We use the name  TSC1 2++ to emphasize that these are cells express TSC1 2 (namely WT). We apologize for this misunderstanding ,