title: mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress.
abstract: Reduction of translational fidelity often occurs in cells with high rates of protein synthesis, generating defective ribosomal products. If not removed, such aberrant proteins can be a major source of cellular stress causing human diseases. Here, we demonstrate that mTORC1 promotes the formation of immunoproteasomes for efficient turnover of defective proteins and cell survival. mTORC1 sequesters precursors of immunoproteasome β subunits via PRAS40. When activated, mTORC1 phosphorylates PRAS40 to enhance protein synthesis and simultaneously to facilitate the assembly of the β subunits for forming immunoproteasomes. Consequently, the PRAS40 phosphorylations play crucial roles in clearing aberrant proteins that accumulate due to mTORC1 activation. Mutations of RAS, PTEN, and TSC1, which cause mTORC1 hyperactivation, enhance immunoproteasome formation in cells and tissues. Those mutations increase cellular dependence on immunoproteasomes for stress response and survival. These results define a mechanism by which mTORC1 couples elevated protein synthesis with immunoproteasome biogenesis to protect cells against protein stress.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Young Sung
authors.initials: YS
authors.lastname: Yun
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Kwan Hyun
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tschida
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Sachs
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Klara E
authors.initials: KE
authors.lastname: Noble-Orcutt
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Branden S
authors.initials: BS
authors.lastname: Moriarity
authors.affiliation: The Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Teng
authors.initials: T
authors.lastname: Ai
authors.affiliation: The Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Ding
authors.affiliation: The Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Williams
authors.affiliation: The Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: David
authors.initials: D
authors.lastname: Largaespada
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: dhkim@umn.edu.
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014176:Protein Biosynthesis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D010750:Phosphoproteins; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C508191:proline-rich Akt substrate, 40 kDa protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins