title: 60-kDa Tat-interactive protein (TIP60) positively regulates Th-inducing POK (ThPOK)-mediated repression of eomesodermin in human CD4+ T cells.
abstract: The abundant expression of IFNγ in Th-inducing POK (ThPOK)-deficient CD4(+) T cells requires the activation of Eomesodermin (Eomes); however, the underlying mechanism of this phenomenon remains unclear. Here we report that ThPOK binds directly to the promoter region of the Eomes gene to repress its expression in CD4(+) T cells. We identified the histone acetyltransferase TIP60 as a co-repressor of ThPOK-target genes, where ectopically expressed TIP60 increased ThPOK protein stability by promoting its acetylation at its Lys(360) residue to then augment the transcriptional repression of Eomes. Moreover, knockdown of endogenous TIP60 abolished the stabilization of ThPOK in CD4(+) T cells, which led to the transcriptional activation of Eomes and increased production of IFNγ. Our results reveal a novel pathway by which TIP60 and ThPOK synergistically suppresses Eomes function and IFNγ production, which could contribute to the regulation of inflammation.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 411 Hefei Road, Shanghai 200025, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Li
authors.forename: Andy
authors.initials: A
authors.lastname: Tsun
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Gao
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Han
authors.forename: Yayi
authors.initials: Y
authors.lastname: Gao
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Zhengju
authors.initials: Z
authors.lastname: Yao
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D000107:Acetylation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000074443:Lysine Acetyltransferase 5; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D055550:Protein Stability; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C491199:EOMES protein, human; C573415:IFNG protein, human; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; C484225:ZBTB7B protein, human; D007371:Interferon-gamma; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5
keywords: Acetylation; Eomesodermin; Histone Acetylase; Inflammation; Protein Stability; T Cell; TIP60; ThPOK; Transcription Regulation