title: The protein level of PGC-1α, a key metabolic regulator, is controlled by NADH-NQO1.
abstract: PGC-1α is a key transcription coactivator regulating energy metabolism in a tissue-specific manner. PGC-1α expression is tightly regulated, it is a highly labile protein, and it interacts with various proteins--the known attributes of intrinsically disordered proteins (IDPs). In this study, we characterize PGC-1α as an IDP and demonstrate that it is susceptible to 20S proteasomal degradation by default. We further demonstrate that PGC-1α degradation is inhibited by NQO1, a 20S gatekeeper protein. NQO1 binds and protects PGC-1α from degradation in an NADH-dependent manner. Using different cellular physiological settings, we also demonstrate that NQO1-mediated PGC-1α protection plays an important role in controlling both basal and physiologically induced PGC-1α protein level and activity. Our findings link NQO1, a cellular redox sensor, to the metabolite-sensing network that tunes PGC-1α expression and activity in regulating energy metabolism.
authors: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors: Yaarit
authors: Y
authors: Adamovich
authors: Amir
authors: A
authors: Shlomai
authors: Peter
authors: P
authors: Tsvetkov
authors: Kfir B
authors: KB
authors: Umansky
authors: Nina
authors: N
authors: Reuven
authors: Jennifer L
authors: JL
authors: Estall
authors: Bruce M
authors: BM
authors: Spiegelman
authors: Yosef
authors: Y
authors: Shaul
mesh_terms: D000818:Animals; D002460:Cell Line / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D001728:Dicumarol / Q000494:pharmacology; D005215:Fasting; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032446:Myoblasts / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D009243:NAD; D001728:Dicumarol; D003513:Cycloheximide; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse; D046988:Proteasome Endopeptidase Complex
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