| Autor: |
Su KH; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA., Cao J; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA., Tang Z; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.; Graduate programs, Department of Molecular &Biomedical Sciences, The University of Maine, 5735 Hitchner Hall, Orono, Maine 04469, USA., Dai S; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA., He Y; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA., Sampson SB; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA., Benjamin IJ; Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA., Dai C; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. |
| Abstrakt: |
To cope with proteotoxic stress, cells attenuate protein synthesis. However, the precise mechanisms underlying this fundamental adaptation remain poorly defined. Here we report that mTORC1 acts as an immediate cellular sensor of proteotoxic stress. Surprisingly, the multifaceted stress-responsive kinase JNK constitutively associates with mTORC1 under normal growth conditions. On activation by proteotoxic stress, JNK phosphorylates both RAPTOR at S863 and mTOR at S567, causing partial disintegration of mTORC1 and subsequent translation inhibition. Importantly, HSF1, the central player in the proteotoxic stress response (PSR), preserves mTORC1 integrity and function by inactivating JNK, independently of its canonical transcriptional action. Thereby, HSF1 translationally augments the PSR. Beyond promoting stress resistance, this intricate HSF1-JNK-mTORC1 interplay, strikingly, regulates cell, organ and body sizes. Thus, these results illuminate a unifying mechanism that controls stress adaptation and growth. |
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