title: Modulation of STAT3 folding and function by TRiC/CCT chaperonin.
abstract: Signal transducer and activator of transcription 3 (Stat3) transduces signals of many peptide hormones from the cell surface to the nucleus and functions as an oncoprotein in many types of cancers, yet little is known about how it achieves its native folded state within the cell. Here we show that Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. TRiC binding to Stat3 was mediated, at least in part, by TRiC subunit CCT3. Stat3 binding to TRiC mapped predominantly to the β-strand rich, DNA-binding domain of Stat3. Notably, enhancing Stat3 binding to TRiC by engineering an additional TRiC-binding domain from the von Hippel-Lindau protein (vTBD), at the N-terminus of Stat3, further increased its affinity for TRiC as well as its function, as determined by Stat3's ability to bind to its phosphotyrosyl-peptide ligand, an interaction critical for Stat3 activation. Thus, Stat3 levels and function are regulated by TRiC and can be modulated by manipulating its interaction with TRiC.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Moses
authors.initials: M
authors.lastname: Kasembeli
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Wilson Chun Yu
authors.initials: WC
authors.lastname: Lau
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Soung-Hun
authors.initials: SH
authors.lastname: Roh
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: T Kris
authors.initials: TK
authors.lastname: Eckols
authors.affiliation: Department of Biology and the BioX Program, Stanford University, Stanford, California, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America; Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
mesh_terms: D000818:Animals; D056404:Chaperonin Containing TCP-1 / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: C533298:CCT2 protein, human; C533299:CCT3 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D056404:Chaperonin Containing TCP-1; C497446:VHL protein, human
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