Faculty Collaboration Database

Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases. Mol Cell Biol 2016 Sep 15;36(18):2403-17

Date

06/30/2016

Pubmed ID

27354066

Pubmed Central ID

PMC5007788

DOI

10.1128/MCB.00292-16

Scopus ID

2-s2.0-84988336071 (requires institutional sign-in at Scopus site)   53 Citations

Abstract

Heat shock factor 1 (HSF1) monitors the structural integrity of the proteome. Phosphorylation at S326 is a hallmark for HSF1 activation, but the identity of the kinase(s) phosphorylating this site has remained elusive. We show here that the dietary agent phenethyl isothiocyanate (PEITC) inhibits heat shock protein 90 (Hsp90), the main negative regulator of HSF1; activates p38 mitogen-activated protein kinase (MAPK); and increases S326 phosphorylation, trimerization, and nuclear translocation of HSF1, and the transcription of a luciferase reporter, as well as the endogenous prototypic HSF1 target Hsp70. In vitro, all members of the p38 MAPK family rapidly and stoichiometrically catalyze the S326 phosphorylation. The use of stable knockdown cell lines and inhibitors indicated that among the p38 MAPKs, p38γ is the principal isoform responsible for the phosphorylation of HSF1 at S326 in cells. A protease-mass spectrometry approach confirmed S326 phosphorylation and unexpectedly revealed that p38 MAPK also catalyzes the phosphorylation of HSF1 at S303/307, previously known repressive posttranslational modifications. Thus, we have identified p38 MAPKs as highly efficient catalysts for the phosphorylation of HSF1. Furthermore, our findings suggest that the magnitude and persistence of activation of p38 MAPK are important determinants of the extent and duration of the heat shock response.

Author List

Dayalan Naidu S, Sutherland C, Zhang Y, Risco A, de la Vega L, Caunt CJ, Hastie CJ, Lamont DJ, Torrente L, Chowdhry S, Benjamin IJ, Keyse SM, Cuenda A, Dinkova-Kostova AT

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
Cell Line
DNA-Binding Proteins
HSP70 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
HeLa Cells
Heat Shock Transcription Factors
Humans
Isothiocyanates
Mice
Mouse Embryonic Stem Cells
Phosphorylation
Protein Multimerization
Protein Transport
Serine
Transcription Factors
Transcription, Genetic
p38 Mitogen-Activated Protein Kinases