Activation of Gene Transcription by Heat Shock Protein 27 May Contribute to Its Neuronal Protection

Abstract

Heat shock proteins are up-regulated as a physiological response to stressful stimuli and generally function as molecular chaperones for improperly folded protein substrates. The small heat shock protein HSP27 (or HSPB1) has multiple cytoplasmic roles. HSP27 also can translocate to the nucleus in response to stress, but the functional significance of this nuclear distribution has not been elucidated. We have previously implicated HSP27 as a genetic modifier of spinocerebellar ataxia 17 (SCA17), a neurological disease caused by a polyglutamine expansion in the TATA-binding protein (TBP). Altered expression of HSP27 is also found in cell models of other polyglutamine diseases, including Huntington disease as well as SCA3 and SCA7. Here, we show that Hsp27, unlike Hsp70, is not detected in mutant TBP aggregates in primary cerebellar granule neurons from transgenic SCA17 mice. Although HSP27 overexpression does not reduce the aggregation of cotransfected mutant TBP containing 105 glutamines, it potentiates activated transcription from both TATA-containing and TATA-lacking promoters. Neither HSP40 nor HSP70 elicits the same transcriptional effect. Moreover, HSP27 interacts with the transcription factor SP1, and coexpression of SP1 and nuclear localization signal-tagged HSP27 synergistically activates reporter constructs for the SP1-responsive neurotrophic receptor genes Ngfrp75 and TRKA. Overexpression of nuclear localization signal-tagged HSP27 also rescues mutant TBP-mediated down-regulation of TrkA in a PC12 cell model of SCA17. These results indicate that nuclear HSP27 can modulate SP1-dependent transcriptional activity to promote neuronal protection. Heat shock proteins are up-regulated as a physiological response to stressful stimuli and generally function as molecular chaperones for improperly folded protein substrates. The small heat shock protein HSP27 (or HSPB1) has multiple cytoplasmic roles. HSP27 also can translocate to the nucleus in response to stress, but the functional significance of this nuclear distribution has not been elucidated. We have previously implicated HSP27 as a genetic modifier of spinocerebellar ataxia 17 (SCA17), a neurological disease caused by a polyglutamine expansion in the TATA-binding protein (TBP). Altered expression of HSP27 is also found in cell models of other polyglutamine diseases, including Huntington disease as well as SCA3 and SCA7. Here, we show that Hsp27, unlike Hsp70, is not detected in mutant TBP aggregates in primary cerebellar granule neurons from transgenic SCA17 mice. Although HSP27 overexpression does not reduce the aggregation of cotransfected mutant TBP containing 105 glutamines, it potentiates activated transcription from both TATA-containing and TATA-lacking promoters. Neither HSP40 nor HSP70 elicits the same transcriptional effect. Moreover, HSP27 interacts with the transcription factor SP1, and coexpression of SP1 and nuclear localization signal-tagged HSP27 synergistically activates reporter constructs for the SP1-responsive neurotrophic receptor genes Ngfrp75 and TRKA. Overexpression of nuclear localization signal-tagged HSP27 also rescues mutant TBP-mediated down-regulation of TrkA in a PC12 cell model of SCA17. These results indicate that nuclear HSP27 can modulate SP1-dependent transcriptional activity to promote neuronal protection. Protein misfolding is a characteristic feature of multiple neurodegenerative disorders, including the polyglutamine (polyQ) 3The abbreviations used are: polyQpolyglutamineHSPheat shock proteinTBPTATA-binding proteinSCAspinocerebellar ataxiaNLSnuclear localization signalEGFPenhanced green fluorescent protein. diseases, which are caused by expansion of a CAG or mixed CAA/CAG trinucleotide repeat in the coding region of at least nine unrelated genes. Various heat shock proteins (HSPs), as well as ubiquitin, proteasomal subunits, and autophagic markers, have been detected in intracellular aggregates formed by mutant polyQ proteins expressed in cultured cells, transgenic mice, and patient brains, indicating that these structures engage the cellular response to misfolded protein (1Sakahira H. Breuer P. Hayer-Hartl M.K. Hartl F.U. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 16412-16418Crossref PubMed Scopus (199) Google Scholar). Intriguingly, the time-dependent increase in polyQ aggregate load negatively correlates with the neuronal expression of certain HSPs in multiple mouse models (2Helmlinger D. Yvert G. Picaud S. Merienne K. Sahel J. Mandel J.L. Devys D. Hum. Mol. Genet. 2002; 11: 3351-3359Crossref PubMed Scopus (74) Google Scholar, 3Merienne K. Helmlinger D. Perkin G.R. Devys D. Trottier Y. J. Biol. Chem. 2003; 278: 16957-16967Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 4Hay D.G. Sathasivam K. Tobaben S. Stahl B. Marber M. Mestril R. Mahal A. Smith D.L. Woodman B. Bates G.P. Hum. Mol. Genet. 2004; 13: 1389-1405Crossref PubMed Scopus (282) Google Scholar, 5Orr A.L. Huang S. Roberts M.A. Reed J.C. Li S. Li X.J. J. Biol. Chem. 2008; 283: 16027-16036Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 6Friedman M.J. Shah A.G. Fang Z.H. Ward E.G. Warren S.T. Li S. Li X.J. Nat. Neurosci. 2007; 10: 1519-1528Crossref PubMed Scopus (136) Google Scholar). Although the pathological role of polyQ aggregates remains controversial and could be disease-specific, the therapeutic potential of manipulating HSP expression has been staked largely on the possibility of reducing toxicity by limiting the misfolding and/or promoting the clearance of polyQ-expanded proteins. polyglutamine heat shock protein TATA-binding protein spinocerebellar ataxia nuclear localization signal enhanced green fluorescent protein. HSPs contribute to normal cell physiology and are crucial components of the cellular stress response. Many HSPs serve as molecular chaperones to facilitate folding or refolding of protein substrates that otherwise would be targeted for degradation. The HSP70 family, comprising constitutive and inducible members, is prominently involved in the proper folding of both nascent and mature proteins. Co-chaperones, such as HSP40 proteins and BAG1, directly stimulate the intrinsic ATPase activity of HSP70 that is required for these processes (7Fink A.L. Physiol. Rev. 1999; 79: 425-449Crossref PubMed Scopus (875) Google Scholar). As part of its collaboration, HSP40 mediates the initial recognition of conformationally immature (8Fan C.Y. Lee S. Cyr D.M. Cell Stress Chaperones. 2003; 8: 309-316Crossref PubMed Scopus (261) Google Scholar) or misfolded (1Sakahira H. Breuer P. Hayer-Hartl M.K. Hartl F.U. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 16412-16418Crossref PubMed Scopus (199) Google Scholar, 8Fan C.Y. Lee S. Cyr D.M. Cell Stress Chaperones. 2003; 8: 309-316Crossref PubMed Scopus (261) Google Scholar) substrates and delivers these client proteins to HSP70 (8Fan C.Y. Lee S. Cyr D.M. Cell Stress Chaperones. 2003; 8: 309-316Crossref PubMed Scopus (261) Google Scholar). Some stress-induced proteins, including HSP27, which is alternatively referred to as Hsp25 in mice or HSPB1 in general, can also modulate cell death by antagonizing various steps in apoptotic pathways (9Dierick I. Irobi J. De Jonghe P. Timmerman V. Ann. Med. 2005; 37: 413-422Crossref PubMed Scopus (49) Google Scholar, 10Garrido C. Brunet M. Didelot C. Zermati Y. Schmitt E. Kroemer G. Cell Cycle. 2006; 5: 2592-2601Crossref PubMed Scopus (563) Google Scholar). We have shown previously that polyQ-expanded TBP causes down-regulation of Hsp27, resulting in diminished neurite outgrowth in PC12 cells and neuritic defects in primary neurons cultured from SCA17 transgenic mice (6Friedman M.J. Shah A.G. Fang Z.H. Ward E.G. Warren S.T. Li S. Li X.J. Nat. Neurosci. 2007; 10: 1519-1528Crossref PubMed Scopus (136) Google Scholar). Although HSP27 performs critical functions in the cytoplasm that promote neuronal viability and neuritic integrity (11Williams K.L. Rahimtula M. Mearow K.M. J. Neurosci. Res. 2006; 84: 716-723Crossref PubMed Scopus (46) Google Scholar, 12Stetler R.A. Cao G. Gao Y. Zhang F. Wang S. Weng Z. Vosler P. Zhang L. Signore A. Graham S.H. Chen J. J. Neurosci. 2008; 28: 13038-13055Crossref PubMed Scopus (120) Google Scholar), it also accumulates in neuronal nuclei in response to stress (13McClaren M. Isseroff R.R. J. Invest. Dermatol. 1994; 102: 375-381Crossref PubMed Scopus (61) Google Scholar, 14Adhikari A.S. Sridhar Rao K. Rangaraj N. Parnaik V.K. Mohan Rao C. Exp. Cell Res. 2004; 299: 393-403Crossref PubMed Scopus (73) Google Scholar, 15Bryantsev A.L. Kurchashova S.Y. Golyshev S.A. Polyakov V.Y. Wunderink H.F. Kanon B. Budagova K.R. Kabakov A.E. Kampinga H.H. Biochem. J. 2007; 407: 407-417Crossref PubMed Scopus (80) Google Scholar). However, the role of nuclear HSP27 in neuronal protection remains unclear. Here, we provide evidence that nuclear HSP27 interacts with the transcription factor SP1 and stimulates SP1-dependent gene expression. Moreover, in a PC12 cell model of SCA17, overexpression of HSP27 rescues decreased expression of the neurotrophic receptor TrkA (tyrosine kinase receptor A), which is transcriptionally regulated by SP1. These results support a novel role for nuclear HSP27 in transcriptional activation and suggest that down-regulation of HSPs in the polyQ diseases, as has been widely observed, could directly impact gene expression. Antibodies against TBP included N-12 (Santa Cruz Biotechnology) and 1TBP18 (QED Bioscience, San Diego, CA). Other commercial antibodies utilized were against HSPB1 (C20, Santa Cruz Biotechnology), phospho-HSPB1 (2401, Cell Signaling), HSP70 (W27, Santa Cruz Biotechnology), HSP90 (AC88, Stressgen), hemagglutinin tag (12CA5, Roche Applied Science), γ-tubulin (GTU-88, Sigma), SP1 (PEP2, Santa Cruz Biotechnology), TrkA (06-574, Upstate), His tag (H-15, Santa Cruz Biotechnology), and glyceraldehyde-3-phosphate dehydrogenase (G8795, Sigma). Hoechst 33258 (Molecular Probes) was used for nuclear labeling. Transfections were performed with Lipofectamine 2000 (Invitrogen). Constructs encoding hemagglutinin-tagged HSP40 and HSP70 have been described previously (5Orr A.L. Huang S. Roberts M.A. Reed J.C. Li S. Li X.J. J. Biol. Chem. 2008; 283: 16027-16036Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). Human HSP27 cDNA was ligated into the pEBV-HisA mammalian expression vector to generate His-HSP27. His-NLS-HSP27 was derived by in-frame insertion of a fragment encoding the SV40 large T antigen NLS. Human embryonic kidney HEK 293 cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin. For stably transfected PC12 cells, Dulbecco's modified Eagle's medium was supplemented with 10% horse serum, 5% fetal bovine serum, and antibiotics. Cerebellar granule neurons were cultured from postnatal day 7 transgenic SCA17 mice as described previously (6Friedman M.J. Shah A.G. Fang Z.H. Ward E.G. Warren S.T. Li S. Li X.J. Nat. Neurosci. 2007; 10: 1519-1528Crossref PubMed Scopus (136) Google Scholar). After 10 days in vitro, cerebellar neurons were fixed with 4% paraformaldehyde and stained with anti-TBP and anti-HSP antibodies, whereas nuclei were labeled with Hoechst. Minimal (−99 to +13) and proximal (−172 to +13) human HSP27 promoter sequences used to generate DsRed reporter constructs have been described previously (16Oesterreich S. E. S.A. Biochem. Res. PubMed Scopus Google Scholar). Ngfrp75 promoter fragment to and a proximal human promoter fragment to both of which feature multiple SP1 were also into The was from a previously S.H. A.L. H. S. Rao M. Li H. Li X.J. Mol. Biol. 2002; PubMed Scopus Google Scholar), and the was as a and DsRed reporter constructs were cotransfected with the expression in HEK with were performed in HEK 293 were in and were as previously M.J. Wang Li X.J. Li S. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar). was performed as described previously (6Friedman M.J. Shah A.G. Fang Z.H. Ward E.G. Warren S.T. Li S. Li X.J. Nat. 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As is cytoplasmic in HEK 293 cells we nuclear HSP27 could this of HSP27 to the nucleus also in of and in cotransfected cells the expression of transfected mutant TBP in the of HSP27 be transcriptionally we performed for TBP in cells that were cotransfected with and vector or His-NLS-HSP27 that the we were to for normal and mutant the of nuclear HSP27, we increase in the expression of TBP to that of TBP and expression of transfected TBP was the of the promoter in the we that nuclear HSP27 stimulate transcription from this the and to this we performed a reporter in which the promoter expression of reporter whereas HSP70 not have a and HSP40 expression. of the promoter was in the of His-NLS-HSP27 not These results indicate that HSP27 can modulate transcriptional activity and the of and coexpression of of TATA-containing gene by HSP27 reporter HEK 293 cells cotransfected with the reporter and HSP or or and reporter performed in HEK cells with DsRed reporter constructs the HSP27 or proximal promoter in and show expression of TBP and HSP27 in of cells for reporter as a The of the human HSP27 promoter in is to a (16Oesterreich S. 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Moreover, of SP1 and in activation of the Ngfrp75 and of the Ngfrp75 and by HSP27 of from transfected HEK cells used for reporter of hemagglutinin-tagged proteins and and indicate transfected HSP27 or of expression constructs were transfected for reporter to the expression used as a and reporter activation by of HSP27 enhanced its of reporter gene expression. reporter activation of the Ngfrp75 and by coexpression of SP1 and The of HSP27 transfected for in was of that used in B. we the potential of nuclear HSP27 in SCA17 We have previously that PC12 cells stably transfected with show a neurite outgrowth in response to factor (6Friedman M.J. Shah A.G. Fang Z.H. Ward E.G. Warren S.T. Li S. Li X.J. Nat. Neurosci. 2007; 10: 1519-1528Crossref PubMed Scopus (136) Google Scholar), and we have detected down-regulation of TrkA in these cells as well as in from SCA17 transgenic mice A.G. M.J. Huang S. Roberts M. Li X.J. Li S. Hum. Mol. Genet. Scholar). we the of nuclear targeted HSP27 on TrkA expression in PC12 cell model of SCA17 the of TrkA in PC12 cells also the expression of TrkA in cells and As we have previously that is in cellular and mouse models of SCA17 (6Friedman M.J. Shah A.G. Fang Z.H. Ward E.G. Warren S.T. Li S. Li X.J. Nat. Neurosci. 2007; 10: 1519-1528Crossref PubMed Scopus (136) Google Scholar), we the nuclear of in the of polyQ-expanded TBP could be detected in the nuclei of or PC12 cells by However, of from heat shock at increase in nuclear was in but not PC12 cells nuclear of in response to heat shock was not in and in nuclear be to of the small which is to directly with its nuclear D. K. J. Biol. 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