mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress

• Published in: Molecular cell Vol. 61; no. 4; pp. 625 - 639
• Main Authors: Yun, Young Sung, Kim, Kwan Hyun, Tschida, Barbara, Sachs, Zohar, Noble-Orcutt, Klara E., Moriarity, Branden S., Ai, Teng, Ding, Rui, Williams, Jessica, Chen, Liqiang, Largaespada, David, Kim, Do-Hyung
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-02-2016
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Survival; HCT116 Cells; HEK293 Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes - metabolism; Mutation; Phosphoproteins - metabolism; Phosphorylation; Proteasome Endopeptidase Complex - metabolism; Protein Biosynthesis; PTEN Phosphohydrolase - genetics; ras Proteins - genetics; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - genetics
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.01.013

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.
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•mTORC1 binds to immunoproteasome β subunit precursors via PRAS40•mTORC1 promotes immunoproteasome formation via PRAS40 phosphorylation•Immunoproteasomes are important for viability of mTORC1-hyperactive cells•The mTORC1-immunoproteasome pathway is important for cell survival against stress
Defective ribosomal products accumulate as a result of reduced fidelity of translation when protein synthesis rates increase. In this report, Yun et al. demonstrate a mechanism by which mTORC1 promotes formation of immunoproteasomes, the inducible type of proteasomes, to couple elevated protein synthesis with efficient turnover of defective proteins.