The Protein Level of PGC-1α, a Key Metabolic Regulator, Is Controlled by NADH-NQO1

Author:

Adamovich Yaarit1,Shlomai Amir1,Tsvetkov Peter1,Umansky Kfir B.1,Reuven Nina1,Estall Jennifer L.2,Spiegelman Bruce M.2,Shaul Yosef1

Affiliation:

1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

2. Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Abstract

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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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