Disruption of the vacuolar-type H+-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes
| Autor: | Sandra Kissing, Renate Lüllmann-Rauch, Albert Haas, Uwe Kornak, Eeva-Liisa Eskelinen, Paul Saftig, Sabrina Jabs, Jef K. De Brabander, Atsuhiro Ichihara, Sönke Rudnik, Jörg Heeren, Markus Damme |
|---|---|
| Přispěvatelé: | Biosciences, Biochemistry and Biotechnology, Autophagy |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
ATPase Endocytic cycle Vacuole mTORC1 Insulin PROTON PUMPS AMINO-ACIDS Amino Acids Cells Cultured Mice Knockout ACTIN-BINDING SITE biology PRORENIN RECEPTOR Basic Research Paper Endocytosis Cell biology REGULATES AUTOPHAGY Proton-Translocating ATPases medicine.anatomical_structure Liver Biochemistry lysosome v-H+-ATPase complex biological phenomena cell phenomena and immunity CLEAR NETWORK Intracellular autophagy Endosome Receptors Cell Surface Endosomes Mechanistic Target of Rapamycin Complex 1 03 medical and health sciences Lysosome medicine Animals V-ATPase PROTEIN-KINASE-C Molecular Biology ATP6AP2 MTORC1 V-ATPASE ribosomal protein S6 kinase transcription factor EB Autophagy Cell Biology Fibroblasts Embryo Mammalian 030104 developmental biology MAMMALIAN TARGET Vacuoles Hepatocytes biology.protein 1182 Biochemistry cell and molecular biology CELL-GROWTH Lysosomes |
| Zdroj: | Autophagy, 13(4):670-685 |
| DOI: | 10.6084/m9.figshare.4592098 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|