TY - JOUR
T1 - mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress
AU - Yun, Young Sung
AU - Kim, Kwan Hyun
AU - Tschida, Barbara
AU - Sachs, Zohar
AU - Noble-Orcutt, Klara E.
AU - Moriarity, Branden S.
AU - Ai, Teng
AU - Ding, Rui
AU - Williams, Jessica
AU - Chen, Liqiang
AU - Largaespada, David
AU - Kim, Do Hyung
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/2/18
Y1 - 2016/2/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958675781&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958675781&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2016.01.013
DO - 10.1016/j.molcel.2016.01.013
M3 - Article
C2 - 26876939
AN - SCOPUS:84958675781
SN - 1097-2765
VL - 61
SP - 625
EP - 639
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -