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

Young Sung Yun, Kwan Hyun Kim, Barbara Tschida, Zohar Sachs, Klara E. Noble-Orcutt, Branden S. Moriarity, Teng Ai, Rui Ding, Jessica Williams, Liqiang Chen, David Largaespada, Do Hyung Kim

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)625-639
Number of pages15
JournalMolecular Cell
Volume61
Issue number4
DOIs
StatePublished - Feb 18 2016

Bibliographical note

Funding Information:
We thank C. Tucker for yeast two-hybrid screen; V. Stambolic for Pten MEFs; D. Kwiatkowski for Tsc1 MEFs and bladder cancer cells; B. Viollet for Ampk MEFs; D. Ferrington, H. Towle, A. Hertzel, and Kim lab members for critical reading and helpful comments; and R. Foncea for lentivirus prep. This study was supported by the Korea Research Foundation (KRF-2008-357-C00121) (to Y.S.Y.), the Center for Drug Design at the University of Minnesota (to L.C.), the NIH (DK050456, GM097057), and the Department of Defense (W81XWH-13-1-0060) (to D.-.H.K.).

Funding Information:
We thank C. Tucker for yeast two-hybrid screen; V. Stambolic for Pten MEFs; D. Kwiatkowski for Tsc1 MEFs and bladder cancer cells; B. Viollet for Ampk MEFs; D. Ferrington, H. Towle, A. Hertzel, and Kim lab members for critical reading and helpful comments; and R. Foncea for lentivirus prep. This study was supported by the Korea Research Foundation (KRF - 2008-357-C00121 ) (to Y.S.Y.), the Center for Drug Design at the University of Minnesota (to L.C.), the NIH ( DK050456 , GM097057 ), and the Department of Defense ( W81XWH-13-1-0060 ) (to D.-.H.K.).

Publisher Copyright:
© 2016 Elsevier Inc.

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