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J. Biol. Chem. 285 (35): 27385-27395

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

mTORC1 Links Protein Quality and Quantity Control by Sensing Chaperone Availability*Formula {diamondsuit}

Shu-Bing Qian{ddagger}1, Xingqian Zhang{ddagger}, Jun Sun{ddagger}, Jack R. Bennink§, Jonathan W. Yewdell§, , and Cam Patterson2

From the {ddagger}Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853,
the §Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and
the McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599

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Abstract: Balanced protein synthesis and degradation are crucial for proper cellular function. Protein synthesis is tightly coupled to energy status and nutrient levels by the mammalian target of rapamycin complex 1 (mTORC1). Quality of newly synthesized polypeptides is maintained by the molecular chaperone and ubiquitin-proteasome systems. Little is known about how cells integrate information about the quantity and quality of translational products simultaneously. We demonstrate that cells distinguish moderate reductions in protein quality from severe protein misfolding using molecular chaperones to differentially regulate mTORC1 signaling. Moderate reduction of chaperone availability enhances mTORC1 signaling, whereas stress-induced complete depletion of chaperoning capacity suppresses mTORC1 signaling. Molecular chaperones regulate mTORC1 assembly in coordination with nutrient availability. This mechanism enables mTORC1 to rapidly detect and respond to environmental cues while also sensing intracellular protein misfolding. The tight linkage between protein quality and quantity control provides a plausible mechanism coupling protein misfolding with metabolic dyshomeostasis.

Key Words: Metabolism • mTOR • mTOR Complex (mTORC) • Protein Degradation • Protein Synthesis • Molecular Chaperone System • Nutrients • Protein Quality Control • Stress

Received for publication March 8, 2010. Revision received May 27, 2010.

1 To whom correspondence may be addressed: 301 Biotech, Cornell University, Ithaca, NY 14853. E-mail: sq38{at}cornell.edu.

2 To whom correspondence may be addressed: 8200 Medical Biomolecular Research Bldg., Chapel Hill, NC 27599. E-mail: cpatters{at}med.unc.edu.

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