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.
Keywords:
Acetylation; Eomesodermin; Histone Acetylase; Inflammation; Protein Stability; T Cell; TIP60; ThPOK; Transcription Regulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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HEK293 Cells
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / immunology
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Histone Acetyltransferases / metabolism*
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Humans
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Lysine Acetyltransferase 5
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Promoter Regions, Genetic / genetics
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Promoter Regions, Genetic / immunology
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Protein Stability
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Repressor Proteins / genetics
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Repressor Proteins / immunology
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Repressor Proteins / metabolism*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
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T-Box Domain Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transcription Factors / metabolism*
Substances
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DNA-Binding Proteins
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EOMES protein, human
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IFNG protein, human
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Repressor Proteins
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T-Box Domain Proteins
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Transcription Factors
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ZBTB7B protein, human
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Interferon-gamma
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Histone Acetyltransferases
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KAT5 protein, human
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Lysine Acetyltransferase 5