mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy
Abstract
Lack of nutrients or growth factors rapidly inhibits mTOR kinase and stimulates overall protein breakdown by autophagy, which provides amino acids for new protein synthesis and energy production. Here, we demonstrate that mTOR inhibition also rapidly increases overall protein degradation by the ubiquitin proteasome system by enhancing the ubiquitination of many cell proteins. These findings demonstrate a new general mechanism regulating overall protein breakdown in mammalian cells. This rapid activation of proteolysis not only slows growth and provides essential amino acids upon starvation, but also stimulates ubiquitin-dependent degradation of certain growth-related proteins, including HMG-CoA synthase, which is critical for cholesterol biosynthesis. Accelerated degradation of such proteins represents a new mechanism for rapid suppression of anabolic processes when mTORC1 activity decreases.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- December 2015
- DOI:
- 10.1073/pnas.1521919112
- Bibcode:
- 2015PNAS..11215790Z