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Disruption of the vacuolar-type H(+)-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes.

Item Type:Article
Title:Disruption of the vacuolar-type H(+)-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes.
Creators Name:Kissing, S. and Rudnik, S. and Damme, M. and Luellmann-Rauch, R. and Ichihara, A. and Kornak, U. and Eskelinen, E.L. and Jabs, S. and Heeren, J. and De Brabander, J.K. and Haas, A. and Saftig, P.
Abstract:The vacuolar-type H(+)-translocating ATPase (v-H(+)-ATPase) has been implicated in the amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (MTORC1), an important regulator of macroautophagy. To reveal the mechanistic links between the v-H(+)-ATPase and MTORC1 we destablilized v-H(+)-ATPase complexes in mouse liver cells by induced deletion of the essential chaperone ATP6AP2. ATP6AP2-mutants are characterized by massive accumulation of endocytic and autophagic vacuoles in hepatocytes. This cellular phenotype was not caused by a block in endocytic maturation or an impaired acidification. However, the degradation of LC3-II in the knockout hepatocytes appeared to be reduced. When v-H(+)-ATPase levels were decreased, we observed lysosome association of MTOR and normal signaling of MTORC1 despite an increase in autophagic marker proteins. To better understand why MTORC1 can be active when v-H(+)-ATPase is depleted, the activation of MTORC1 was analyzed in ATP6AP2-deficient fibroblasts. In these cells, very little amino acid-elicited activation of MTORC1 was observed. In contrast, insulin did induce MTORC1 activation, which still required intracellular amino acid stores. These results suggest that in vivo the regulation of macroautophagy depends not only on v-H(+)-ATPase-mediated regulation of MTORC1.
Keywords:ATP6AP2, Autophagy, Lysosome, MTORC1, Ribosomal Protein S6 Kinase, Transcription Factor EB, v-H+-ATPase Complex, Animals, Mice
Source:Autophagy
ISSN:1554-8627
Publisher:Taylor & Francis (U.S.A.)
Volume:13
Number:4
Page Range:670-685
Date:April 2017
Official Publication:https://doi.org/10.1080/15548627.2017.1280216
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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