title: mTORC1 links protein quality and quantity control by sensing chaperone availability.
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.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853. Electronic address: sq38@cornell.edu.
authors.forename: Shu-Bing
authors.initials: SB
authors.lastname: Qian
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853.
authors.forename: Xingqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Bennink
authors.affiliation: Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599. Electronic address: cpatters@med.unc.edu.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D002460:Cell Line; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D017510:Protein Folding; D011506:Proteins; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases