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

55 Scopus citations


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
Issue number4
StatePublished - Feb 18 2016

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© 2016 Elsevier Inc.


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