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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01672-12.

ACKNOWLEDGMENTS

We thank Dina Laznik and Julia Adler for technical assistance.

This study was supported by grant 2007285 from the United States-Israel Binational Science Foundation and by grants from the Israel Science Foundation (grant 551/11). Y.S. is the Oscar and Emma Getz Professor. Y.A. was supported by an EMBO short-term fellowship (2009).