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Molecular and Cellular Biology, April 2003, p. 2953-2968, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2953-2968.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Serine 303 Is a Prerequisite for the Stress-Inducible SUMO Modification of Heat Shock Factor 1

Ville Hietakangas,1,2 Johanna K. Ahlskog,1,3 Annika M. Jakobsson,1,3 Maria Hellesuo,1 Niko M. Sahlberg,1 Carina I. Holmberg,1,{dagger} Andrey Mikhailov,1 Jorma J. Palvimo,4 Lila Pirkkala,1,{ddagger} and Lea Sistonen1,3*

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University,1 Department of Biochemistry and Food Chemistry, University of Turku,2 Department of Biology, Åbo Akademi University, Turku,3 Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, Helsinki, Finland4

Received 15 July 2002/ Returned for modification 29 August 2002/ Accepted 27 January 2003

The heat shock response, which is accompanied by a rapid and robust upregulation of heat shock proteins (Hsps), is a highly conserved protection mechanism against protein-damaging stress. Hsp induction is mainly regulated at transcriptional level by stress-inducible heat shock factor 1 (HSF1). Upon activation, HSF1 trimerizes, binds to DNA, concentrates in the nuclear stress granules, and undergoes a marked multisite phosphorylation, which correlates with its transcriptional activity. In this study, we show that HSF1 is modified by SUMO-1 and SUMO-2 in a stress-inducible manner. Sumoylation is rapidly and transiently enhanced on lysine 298, located in the regulatory domain of HSF1, adjacent to several critical phosphorylation sites. Sumoylation analyses of HSF1 phosphorylation site mutants reveal that specifically the phosphorylation-deficient S303 mutant remains devoid of SUMO modification in vivo and the mutant mimicking phosphorylation of S303 promotes HSF1 sumoylation in vitro, indicating that S303 phosphorylation is required for K298 sumoylation. This finding is further supported by phosphopeptide mapping and analysis with S303/7 phosphospecific antibodies, which demonstrate that serine 303 is a target for strong heat-inducible phosphorylation, corresponding to the inducible HSF1 sumoylation. A transient phosphorylation-dependent colocalization of HSF1 and SUMO-1 in nuclear stress granules provides evidence for a strictly regulated subnuclear interplay between HSF1 and SUMO.

* Corresponding author. Mailing address: Turku Centre for Biotechnology, P.O. Box 123, FIN-20521 Turku, Finland. Phone: 358-2-333 8028. Fax: 358-2-333 8000. E-mail: lea.sistonen{at}btk.utu.fi.

{dagger} Present address: Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Ill.

{ddagger} Present address: Hormos Medical Corp., FIN-20520 Turku, Finland.

Molecular and Cellular Biology, April 2003, p. 2953-2968, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2953-2968.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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