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HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth. Nat Cell Biol 2016 05;18(5):527-39

Date

04/05/2016

Pubmed ID

27043084

Pubmed Central ID

PMC5341796

DOI

10.1038/ncb3335

Scopus ID

2-s2.0-84962086158   34 Citations

Abstract

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.

Author List

Su KH, Cao J, Tang Z, Dai S, He Y, Sampson SB, Benjamin IJ, Dai C

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Body Size
Cell Proliferation
Cell Size
DNA-Binding Proteins
Enzyme Activation
HEK293 Cells
HeLa Cells
Heat Shock Transcription Factors
Heat-Shock Response
Humans
JNK Mitogen-Activated Protein Kinases
Liver
MAP Kinase Signaling System
Mechanistic Target of Rapamycin Complex 1
Mice
Multiprotein Complexes
Organ Size
Phosphorylation
Protein Biosynthesis
Proteins
Stress, Physiological
TOR Serine-Threonine Kinases
Transcription Factors
Transcription, Genetic
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a