title: mTORC1 signaling activates NRF1 to increase cellular proteasome levels.
abstract: Defects in the maintenance of protein homeostasis, or proteostasis, has emerged as an underlying feature of a variety of human pathologies, including aging-related diseases. Proteostasis is achieved through the coordinated action of cellular systems overseeing amino acid availability, mRNA translation, protein folding, secretion, and degradation. The regulation of these distinct systems must be integrated at various points to attain a proper balance. In a recent study, we found that the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway, well known to enhance the protein synthesis capacity of cells while concordantly inhibiting autophagy, promotes the production of more proteasomes. Activation of mTORC1 genetically, through loss of the tuberous sclerosis complex (TSC) tumor suppressors, or physiologically, through growth factors or feeding, stimulates a transcriptional program involving the sterol-regulatory element binding protein 1 (SREBP1) and nuclear factor erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1) transcription factors leading to an increase in cellular proteasome content. As discussed here, our findings suggest that this increase in proteasome levels facilitates both the maintenance of proteostasis and the recovery of amino acids in the face of an increased protein load consequent to mTORC1 activation. We also consider the physiological and pathological implications of this unexpected new downstream branch of mTORC1 signaling.
authors.affiliation: a Department of Genetics and Complex Diseases; Harvard T.H. Chan School of Public Health ; Boston , MA , USA.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: NFE2L1; NRF2; aging; cancer; muscle; neurodegeneration; proteasome; synaptic plasticity