The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan |
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Authors: | Huaize Liu Jie Ding Karl Köhnlein Nadine Urban Alessandro Ori Pablo Villavicencio-Lorini |
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Institution: | 1. Institute of Physiological Chemistry, Martin-Luther University Halle-Wittenberg , Halle, Germany;2. Institute of Nutritional Sciences, Friedrich Schiller University Jena , Jena, Germany;3. Leibniz Institute on Aging, Fritz Lipmann Institute (FLI) , Jena, Germany https://orcid.org/0000-0002-3046-0871;4. Institute of Human Genetics, Martin-Luther University Halle-Wittenberg , Halle, Germany |
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Abstract: | ABSTRACT The AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by sensing the metabolic status of the cell. AMPK is regulated by phosphorylation and dephosphorylation as a result of changing AMP/ATP levels and by removal of inhibitory ubiquitin residues by USP10. In this context, we identified the GID-complex, an evolutionarily conserved ubiquitin-ligase-complex (E3), as a negative regulator of AMPK activity. Our data show that the GID-complex targets AMPK for ubiquitination thereby altering its activity. Cells depleted of GID-subunits mimic a state of starvation as shown by increased AMPK activity and macroautophagic/autophagic flux as well as reduced MTOR activation. Consistently, gid-genes knockdown in C. elegans results in increased organismal lifespan. This study may contribute to understand metabolic disorders such as type 2 diabetes mellitus and morbid obesity and implements alternative therapeutic approaches to alter AMPK activity. |
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Keywords: | AMPK autophagy GID longevity primary cilium ubiquitination |
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