Protein Phosphatase 5 Is a Negative Modulator of Heat Shock Factor 1

The major stress protein transcription factor, heat shock factor (HSF1), is tightly regulated through a multilayered activation-deactivation process involving oligomerization, post-translational modification, and interaction with the heat shock protein (Hsp90)-containing multichaperone complex. Conditions of proteotoxic stress, such as heat shock, trigger reversible assembly of latent HSF1 monomers into DNA-binding homotrimers that bind with high affinity to cognate heat shock elements. Transactivation is a second and independently regulated function of HSF1 that is accompanied by hyperphosphorylation and appears to involve a number of signaling events. Association of HSF1 with Hsp90 chaperone complexes provides additional regulatory complexity, however, not all the co-chaperones have been identified, and the specific molecular interactions throughout the activation/deactivation pathway remain to be determined. Here we demonstrate that protein phosphatase 5 (PP5), a tetratricopeptide domain-containing component of Hsp90-steroid receptor complexes, functions as a negative modulator of HSF1 activity. Physical interactions between PP5 and HSF1-Hsp90 complexes were observed in co-immunoprecipitation and gel mobility supershift experiments. Overexpression of PP5 or activation of endogenous phosphatase activity resulted in diminished HSF1 DNA binding and transcriptional activities, and accelerated recovery. Conversely, microinjection of PP5 antibodies, or inhibition of its phosphatase activity in vivo, significantly delayed trimer disassembly after heat shock. Inhibition of PP5 activity did not activate HSF1 in unstressed cells. These results indicate that PP5 is a negative modulator of HSF1 activity. The major stress protein transcription factor, heat shock factor (HSF1), is tightly regulated through a multilayered activation-deactivation process involving oligomerization, post-translational modification, and interaction with the heat shock protein (Hsp90)-containing multichaperone complex. Conditions of proteotoxic stress, such as heat shock, trigger reversible assembly of latent HSF1 monomers into DNA-binding homotrimers that bind with high affinity to cognate heat shock elements. Transactivation is a second and independently regulated function of HSF1 that is accompanied by hyperphosphorylation and appears to involve a number of signaling events. Association of HSF1 with Hsp90 chaperone complexes provides additional regulatory complexity, however, not all the co-chaperones have been identified, and the specific molecular interactions throughout the activation/deactivation pathway remain to be determined. Here we demonstrate that protein phosphatase 5 (PP5), a tetratricopeptide domain-containing component of Hsp90-steroid receptor complexes, functions as a negative modulator of HSF1 activity. Physical interactions between PP5 and HSF1-Hsp90 complexes were observed in co-immunoprecipitation and gel mobility supershift experiments. Overexpression of PP5 or activation of endogenous phosphatase activity resulted in diminished HSF1 DNA binding and transcriptional activities, and accelerated recovery. Conversely, microinjection of PP5 antibodies, or inhibition of its phosphatase activity in vivo, significantly delayed trimer disassembly after heat shock. Inhibition of PP5 activity did not activate HSF1 in unstressed cells. These results indicate that PP5 is a negative modulator of HSF1 activity. The cellular stress response protects against environmental or physiological perturbations that result in aberrant folding and aggregation of proteins. Stress induces rapid synthesis of a set of molecular chaperones known as heat shock proteins (Hsps) 1The abbreviations used are: Hsp, heat shock protein; Ab, antibody; HSF1, heat shock factor 1; PP5, protein phosphatase 5; EMSA, electrophoretic mobility shift assay; IP, immunoprecipitation; GR, glucocorticoid receptor; TPR, tetratricopeptide repeat; CMV, cytomegalovirus; HSE, heat shock element. 1The abbreviations used are: Hsp, heat shock protein; Ab, antibody; HSF1, heat shock factor 1; PP5, protein phosphatase 5; EMSA, electrophoretic mobility shift assay; IP, immunoprecipitation; GR, glucocorticoid receptor; TPR, tetratricopeptide repeat; CMV, cytomegalovirus; HSE, heat shock element. (1Morimoto R. Tissiers A. Georgopoulos C. Stress Proteins in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1990Google Scholar) that aid the folding, transport, regulation, and degradation of cellular proteins. The highly conserved transcription factor HSF1 is the key regulatory protein responsible for the up-regulation of Hsp expression in higher eukaryotes (1Morimoto R. Tissiers A. Georgopoulos C. Stress Proteins in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1990Google Scholar, 2Christians E.S. Yan L.J. Benjamin I.J. Crit. Care Med. 2002; 30: S43-S50Crossref Scopus (187) Google Scholar, 3Voellmy R. Cell Stress Chaperones. 2004; 9: 122-133Crossref PubMed Scopus (223) Google Scholar). The mechanism of HSF1 regulation is highly complex, involving multifactorial control by phosphorylation, cellular compartmentalization, and protein-protein interaction with chaperone complexes. It is not yet known how these multiple layers of control are integrated to result in cellular regulation of HSF1 and the stress response. HSF1 exists under normal conditions as non-DNA-binding monomers, poised for rapid conversion to homotrimers with high affinity DNA binding activity to the heat shock elements in Hsp gene promoters (4Baler R. Dahl G. Voellmy R. Mol. Cell. Biol. 1993; 13: 2486-2496Crossref PubMed Scopus (390) Google Scholar, 5Sarge K.D. Murphy S.P. Morimoto R.I. Mol. Cell. Biol. 1993; 13: 1392-1407Crossref PubMed Scopus (740) Google Scholar). This oligomeric switching involves rearrangement of hydrophobic interactions between 3 hydrophobic heptad repeats distributed along the HSF1 molecule (4Baler R. Dahl G. Voellmy R. Mol. Cell. Biol. 1993; 13: 2486-2496Crossref PubMed Scopus (390) Google Scholar, 6Westwood J.T. Clos J. Wu C. Nature. 1991; 353: 822-827Crossref PubMed Scopus (307) Google Scholar, 7Westwood J.T. Wu C. Mol. Cell. Biol. 1993; 13: 3481-3486Crossref PubMed Scopus (185) Google Scholar, 8Zuo J. Baler R. Dahl G. Voellmy R. Mol. Cell. 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Several kinases have been reported to phosphorylate HSF1 on specific residues and either enhance or repress its activities, including calcium/calmodulin-dependent protein kinase II (11Holmberg C.I. Hietakangas V. Mikhailov A. Rantanen J.O. Kallio M. Meinander A. Hellman J. Morrice N. MacKintosh C. Morimoto R.I. Eriksson J.E. Sistonen L. EMBO J. 2001; 20: 3800-3810Crossref PubMed Scopus (244) Google Scholar), casein kinase 2 (12Soncin F. Zhang X. Chu B. Wang X. Asea A. Ann Stevenson M. Sacks D.B. Calderwood S.K. Biochem. Biophys. Res. Commun. 2003; 303: 700-706Crossref PubMed Scopus (57) Google Scholar), protein kinase Cα (13Yang R.C. Jao H.C. Huang L.J. Wang S.J. Hsu C. Exp. Cell Res. 2004; 296: 276-284Crossref PubMed Scopus (12) Google Scholar), glycogen synthase kinase 3 (14Xavier I.J. Mercier P.A. McLoughlin C.M. Ali A. Woodgett J.R. Ovsenek N. J. Biol. Chem. 2000; 275: 29147-29152Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 15Chu B. Zhong R. Soncin F. 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Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar, 21Guo Y. Guettouche T. Fenna M. Boellmann F. Pratt W.B. Toft D.O. Smith D.F. Voellmy R. J. Biol. Chem. 2001; 276: 45791-45799Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 22Nair S.C. Toran E.J. Rimerman R.A. Hjermstad S. Smithgall T.E. Smith D.F. Cell Stress Chaperones. 1996; 1: 237-250Crossref PubMed Scopus (196) Google Scholar). The role of Hsp90 chaperone complexes on transcription factor regulation has been most extensively characterized in the experimental model of steroid receptor maturation (23Riggs D. Cox M. Cheung-Flynn J. Prapapanich V. Carrigan P. Smith D. Crit. Rev. Biochem. Mol. Biol. 2004; 39: 279-295Crossref PubMed Scopus (106) Google Scholar, 24Pratt W.B. Toft D.O. Bull. Exp. Biol. Med. 2003; 228: 111-133Crossref Scopus (1239) Google Scholar). Hsp90 is the key molecular chaperone in mature receptor complexes together with p23 and one of the immunophilins (Cyp40, FKBP51, or FKBP52). Assembly of steroid receptor complexes is a highly dynamic process involving Hsp70 and accessory chaperones Hsp40, Hip, and Hop (24Pratt W.B. Toft D.O. Bull. Exp. Biol. Med. 2003; 228: 111-133Crossref Scopus (1239) Google Scholar). Using human and Voellmy and (3Voellmy R. Cell Stress Chaperones. 2004; 9: 122-133Crossref PubMed Scopus (223) Google Scholar, 19Zou J. Guo Y. Guettouche T. Smith D.F. Voellmy R. Cell. 1998; 94: 471-480Abstract Full Text Full Text PDF PubMed Scopus (917) Google Scholar, 21Guo Y. Guettouche T. Fenna M. Boellmann F. Pratt W.B. Toft D.O. Smith D.F. Voellmy R. J. Biol. Chem. 2001; 276: 45791-45799Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar) have Hsp90 with HSF1 monomers, as as HSF1 trimer with complex, and have a model for transcriptional of HSF1 activity by has HSF1 regulation by Hsp90 in the model and reported HSF1 interaction with multiple of the Hsp90 (18Ali A. Bharadwaj S. O'Carroll R. Ovsenek N. Mol. Cell. Biol. 1998; 18: 4949-4960Crossref PubMed Scopus (236) Google Scholar, 20Bharadwaj S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar). and remain associated with the binding HSF1 S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar). to monomers after heat shock accelerated by of Hip, and Hop and delayed by FKBP51, and FKBP52). HSF1 in the of heat shock by microinjection of against Hsp90 and and against of the co-chaperones the DNA-binding of evidence control of has been reported in J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). The molecular interactions and specific of of the Hsp90 in DNA and transcriptional activity, of the HSF1 activation/deactivation has not yet been determined. the with and that the multichaperone interactions that HSF1 with the steroid receptor maturation pathway S.C. Toran E.J. Rimerman R.A. Hjermstad S. Smithgall T.E. Smith D.F. Cell Stress Chaperones. 1996; 1: 237-250Crossref PubMed Scopus (196) Google Scholar). PP5 phosphatase is a major component of steroid and is in the regulation of glucocorticoid receptor and receptor function Pratt W.B. M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Pratt W.B. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, G. 1999; PubMed Scopus Google Scholar, M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Y. S. M. S. 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A. 1994; PubMed Scopus Google Scholar), and Pratt W.B. M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). In were into the with of or and and for 1 to and mobility shift were by as N. Morimoto R.I. PubMed Scopus Google Scholar). gel mobility supershift were into DNA binding a of DNA binding activity and results were in as a of the in DNA binding used for gel mobility shift and were as number of D. D. of D. of D. of number number number number number and number were as (14Xavier I.J. Mercier P.A. McLoughlin C.M. Ali A. Woodgett J.R. Ovsenek N. J. Biol. Chem. 2000; 275: 29147-29152Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 20Bharadwaj S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar). were number or number in and were in and for activity and were the of and PubMed Scopus Google Scholar) as S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar). for were 5 and in in a of with a of protein number were for with 2 of with proteins were with and were by were as (18Ali A. Bharadwaj S. O'Carroll R. Ovsenek N. Mol. Cell. Biol. 1998; 18: 4949-4960Crossref PubMed Scopus (236) Google Scholar, 20Bharadwaj S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar). Overexpression of PP5 HSF1 DNA the role of PP5 in HSF1 regulation, were with Pratt W.B. M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar), for PP5 under control of the of PP5 the of with a to endogenous PP5 after of shock did not of either endogenous or PP5, did of PP5 have effect on the of HSF1, or after heat shock. The activation of HSF1 binding in and PP5 by The of significantly in PP5 to DNA binding activity of transcription such as transcription factor or not were not by expression of PP5, a effect on DNA binding activities in the HSF1 activation in PP5 for or to heat shock The of HSF1 activation to the of PP5, a between increased PP5 and HSF1 The in HSF1 DNA binding activity the phases of heat shock. of heat shock, to by in all that heat shock diminished the of PP5 on the effect of PP5 on the induction of HSF1 by HSF1 activation in PP5 in response to and of the of endogenous and PP5 in control and PP5 in the with in a shock resulted in of PP5 into the 5 and PP5 to endogenous PP5, in and by heat shock. The of the is of the and the of PP5 in the to heat shock not the and the demonstrate the of PP5 with is protein in P.A. J. Ovsenek N. J.T. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), and of PP5 a interaction between these proteins. were to for interaction between endogenous PP5 and of PP5 against HSF1 1 and and of HSF1 against PP5 and a interaction between PP5 and HSF1 in These interactions were in and with or observed in the after heat shock. This that PP5 is a component of Hsp90 with monomeric and trimeric The protein-protein is through interaction between the of PP5 and the of it that PP5 with with to PP5 or HSF1 in or and PP5 in microinjection with HSF1 in a as endogenous of PP5 with HSF1 observed in and 3 and a interaction between PP5 and HSF1 complexes. These evidence of a between PP5 and in HSF1 activity and observed in PP5 1 and of PP5 on HSF1 during recovery. the of HSF1 binding activity between and were either not heat or heat for 1 to recovery and by with of with of or and to heat shock and recovery as of with or Ab, to heat shock and recovery and of co-immunoprecipitation with HSF1 were and and and and of with for 2 to heat shock and recovery. of PP5, or with In were between a 3 and are of PP5 on were with of or of for to a heat shock heat shock. heat shock, were for for to and and were as of for of microinjection of of to heat shock. microinjection of of to heat shock. with for 2 to heat shock. with for 2 to heat shock. control with for 2 to heat shock. a of a to and were were 5 and results are the of PP5 with HSF1 mobility supershift were against PP5 and of HSF1-Hsp90 have observed of complexes with and S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar), results with of of Y. Guettouche T. Fenna M. Boellmann F. Pratt W.B. Toft D.O. Smith D.F. Voellmy R. J. Biol. Chem. 2001; 276: 45791-45799Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). complexes with mobility were observed with against PP5, HSF1, Hip, and This that PP5 is a component of trimeric HSF1 complexes along with and complexes were not by Hop and or control against transcription factor or and were in these to for interactions with the HSF1 however, supershift observed of PP5 on the DNA of and mobility supershift PP5 as a component of the HSF1-Hsp90 and we observed significantly activation of HSF1 DNA binding after expression of PP5 The of were the effect on HSF1 of the specific PP5 phosphatase activity. did not with a of PP5 1997; PubMed Scopus Google Scholar, J. C. C. D. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). in activation of PP5 by of the of Hsp90 the interaction between the and of PP5 in of phosphatase activity M. 2002; PubMed Scopus Google Scholar). The of HSF1 activation in and PP5 with a of the of heat shock a specific of PP5, did not the of HSF1 activation during heat shock, did it activate HSF1 in the of heat shock PP5 appears to HSF1 activity, inhibition of PP5 is not to trigger a specific of T. 2001; PubMed Scopus Google Scholar), did not the or of in HSF1 after of and the of HSF1 activity observed after and activation likely of specific up-regulation of PP5 phosphatase activity. It that the observed in these were of or of endogenous complexes by or the of we used of PP5, and that in the these affinity for Hsp90 in phosphatase activity M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of and diminished HSF1 activity in a as expression of PP5 or the PP5 In addition, of the PP5 Pratt W.B. M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar) effect inhibition of HSF1 observed in these likely of PP5 phosphatase activity of proteins or on endogenous Hsp90 complexes. of PP5 on of HSF1 during of by increased PP5 activity be by a of trimer during or of trimer conversion to monomers during the of during the of recovery heat shock to the of PP5 on disassembly of HSF1 The of HSF1 activation observed after heat shock, and complexes by of recovery in HSF1 activation in PP5 and complexes by and of endogenous PP5 by expression of resulted in accelerated recovery This rapid recovery be of a higher of by increased PP5 activity, or to the that complexes were after heat shock. in the of recovery observed after of or or of the on recovery are specific to effect after inhibition of PP5 in through microinjection of PP5 resulted in a delayed to or with complexes were after complexes in of PP5 the interaction of PP5 with HSF1 that a effect on HSF1 complexes, and the between of PP5 and on HSF1 activity. inhibition of PP5 The on HSF1 recovery by PP5 activation or inhibition in these the phosphatase activity of PP5 to the process of trimer of PP5 on the of DNA binding and transcriptional activities of HSF1 are regulated S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar, J.O. Calderwood S.K. Mol. Cell. Biol. PubMed Scopus Google Scholar, Sistonen L. R.A. Morimoto R.I. PubMed Scopus Google Scholar), we the effect of PP5 on activity of the Hsp70 in by of PP5 2 and not after inhibition of PP5, were observed not by microinjection of however, it by microinjection of and by inhibition of phosphatase activity by in transcription the In all the Hsp70 not significantly in and the of transcription not by these results that PP5 has a negative regulatory role on it is to effect through inhibition of or PP5 its the of trimer results demonstrate that PP5 is a component of the HSF1-Hsp90 complex, and that it functions as a modulator of HSF1 interactions were in as as in supershift HSF1 and PP5 in and that PP5 with HSF1 monomers and supershift of HSF1 by the interaction between PP5 and the trimeric of In these complexes in DNA binding were by against and PP5 is of a chaperone that function to in the for activation and S. Ali A. Ovsenek N. Mol. Cell. Biol. 1999; 19: 8033-8041Crossref PubMed Scopus (144) Google Scholar, 21Guo Y. Guettouche T. Fenna M. Boellmann F. Pratt W.B. Toft D.O. Smith D.F. Voellmy R. J. Biol. Chem. 2001; 276: 45791-45799Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). that a interaction been observed in with Y. Guettouche T. Fenna M. Boellmann F. Pratt W.B. Toft D.O. Smith D.F. Voellmy R. J. Biol. Chem. 2001; 276: 45791-45799Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar), the of not It be that the interactions reported are between endogenous with It is likely that interaction of PP5 with the HSF1-Hsp90 involves between the of PP5 and the of Hsp90 M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), however, between HSF1 and PP5 have not been PP5 associated with HSF1 in a as the endogenous there is a between the observed PP5 activity and the activity of is the function of PP5 in HSF1 results that PP5 is a negative modulator of The experimental to the role of PP5 in to the of or inhibition of PP5 on HSF1 activities in in PP5 did not binding activity by heat shock 1 and and resulted in a rapid of during recovery The on activation and recovery were observed after of endogenous PP5 with the that the phosphatase activity of PP5 a role in negative regulation of of HSF1 activity were observed in a of we that PP5 a regulatory effect under a of environmental stress the of DNA binding inhibition to the of PP5 of the major cellular and or with did not in HSF1 DNA binding activity These that the observed of HSF1 activities were specific to PP5, not to a effect of increased cellular phosphatase activity. It that the on HSF1 in these be by on HSF1-Hsp90 complexes through synthesis of PP5, the activities of the in a number of that the observed in these to in the phosphatase activity of PP5 perturbations of Hsp90 the effect on HSF1 observed after expression of of PP5 with to with and to Hsp90 complexes in the of the PP5 effect on HSF1 activity. and of PP5 phosphatase activity with in experiments. of HSF1 binding to the effect with PP5, that the phosphatase activity HSF1 of its affinity for Hsp90 the complex. It that PP5 interactions with the HSF1-Hsp90 are independent of its or that the are to interactions in This to that PP5 the HSF1-Hsp90 complex, of and of the specific interactions of PP5 the HSF1-Hsp90 complexes be to the mechanism by it HSF1 activity. The inhibition of HSF1 binding most of heat shock activation however, we that PP5 as a of HSF1 that it functions to the in of observed that HSF1 binding not in the of heat shock by inhibition of PP5 with or microinjection of induction observed in response to heat shock and of PP5 phosphatase activity significantly delayed the of HSF1 during recovery. the inhibition of HSF1 in the activation be by of by PP5 activity. gene that PP5 additional role in negative regulation of HSF1 transcriptional activity. Hsp70 activity by of PP5 The results of transcription were with HSF1 DNA binding in transcription is on of binding we PP5 additional on the transcriptional activation its effect on In addition, the that we did not in transcription after PP5 with the of transcriptional regulation of HSF1 through multiple be between the of PP5 in HSF1-Hsp90 complexes, reported and the of PP5 in and receptor Pratt W.B. M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Pratt W.B. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Y. S. M. S. Mol. 2004; 18: PubMed Scopus Google Scholar). The role of PP5 in steroid receptor and its Hsp90 have not been M. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). are on the role of PP5 in regulation, the of PP5 is for signaling Pratt W.B. M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar), it is to signaling G. 1999; PubMed Scopus Google Scholar). PP5 has been reported to transcription S. T. Y. S. M. S. Mol. 2004; 18: PubMed Scopus Google Scholar). It is that there are conserved by PP5 the Hsp90 in the of steroid receptor and HSF1 transcription with steroid there are regulatory for PP5 in HSF1-Hsp90 complexes. The most be HSF1 it is by kinases and is heat shock. it is that PP5 the HSF1 complex. the heat of PP5 a for PP5 in the has on HSF1 regulation is The molecular mechanism by PP5 to HSF1 is under

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