mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress
| Autor: | Teng Ai, Kwan Hyun Kim, Klara E. Noble-Orcutt, Jessica Williams, David A. Largaespada, Do Hyung Kim, Zohar Sachs, Branden S. Moriarity, Barbara R. Tschida, Liqiang Chen, Rui Ding, Young Sung Yun |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Cell Survival mTORC1 Biology Mechanistic Target of Rapamycin Complex 1 medicine.disease_cause Tuberous Sclerosis Complex 1 Protein Article 03 medical and health sciences Mice Protein biosynthesis medicine Animals Humans Phosphorylation Molecular Biology Adaptor Proteins Signal Transducing Mutation TOR Serine-Threonine Kinases Tumor Suppressor Proteins HEK 293 cells PTEN Phosphohydrolase Signal transducing adaptor protein Cell Biology HCT116 Cells Phosphoproteins Cell biology 030104 developmental biology HEK293 Cells Multiprotein Complexes Protein Biosynthesis ras Proteins Signal transduction biological phenomena cell phenomena and immunity Biogenesis Signal Transduction |
| Zdroj: | Molecular cell. 61(4) |
| ISSN: | 1097-4164 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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