title: HSP27 is a ubiquitin-binding protein involved in I-kappaBalpha proteasomal degradation.
abstract: HSP27 is an ATP-independent chaperone that confers protection against apoptosis through various mechanisms, including a direct interaction with cytochrome c. Here we show that HSP27 overexpression in various cell types enhances the degradation of ubiquitinated proteins by the 26S proteasome in response to stressful stimuli, such as etoposide or tumor necrosis factor alpha (TNF-alpha). We demonstrate that HSP27 binds to polyubiquitin chains and to the 26S proteasome in vitro and in vivo. The ubiquitin-proteasome pathway is involved in the activation of transcription factor NF-kappaB by degrading its main inhibitor, I-kappaBalpha. HSP27 overexpression increases NF-kappaB nuclear relocalization, DNA binding, and transcriptional activity induced by etoposide, TNF-alpha, and interleukin 1beta. HSP27 does not affect I-kappaBalpha phosphorylation but enhances the degradation of phosphorylated I-kappaBalpha by the proteasome. The interaction of HSP27 with the 26S proteasome is required to activate the proteasome and the degradation of phosphorylated I-kappaBalpha. A protein complex that includes HSP27, phosphorylated I-kappaBalpha, and the 26S proteasome is formed. Based on these observations, we propose that HSP27, under stress conditions, favors the degradation of ubiquitinated proteins, such as phosphorylated I-kappaBalpha. This novel function of HSP27 would account for its antiapoptotic properties through the enhancement of NF-kappaB activity.
authors.affiliation: INSERM U517, UFR Médecine et Pharmacie, 21033 Dijon, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Parcellier
authors.forename: Elise
authors.initials: E
authors.lastname: Schmitt
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.forename: Daphné
authors.initials: D
authors.lastname: Seigneurin-Berny
authors.forename: Alena
authors.initials: A
authors.lastname: Pance
authors.forename: Aurélie
authors.initials: A
authors.lastname: Chantôme
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Plenchette
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
mesh_terms: D000818:Animals; D017209:Apoptosis; D002850:Chromatography, Gel; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D017930:Genes, Reporter; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D015151:Immunoblotting; D007375:Interleukin-1 / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones; D009097:Multienzyme Complexes / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D003574:Cytochrome c Group; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D020672:I-kappa B Proteins; D007375:Interleukin-1; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; C000606206:Nfkbia protein, rat; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D005047:Etoposide; D005982:Glutathione Transferase; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease