Abstract
Posttranslational modification of proteins within T cell receptor signaling cascades allows T lymphocytes to rapidly initiate an appropriate immune response. Here we report a role for arginine methylation in regulating cytokine gene transcription in the T helper lymphocyte. Inhibition of arginine methylation impaired the expression of several cytokine genes, including the signature type 1 and type 2 helper cytokines, interferon gamma, and interleukin-4. T cell receptor signaling increased expression of the protein arginine methyltransferase PRMT1, which in turn methylated the nuclear factor of activated T cells (NFAT) cofactor protein, NIP45. Arginine methylation of the amino terminus of NIP45 modulated its interaction with NFAT and resulted in augmented cytokine production, while T cells from mice lacking NIP45 had impaired expression of IFNgamma and IL-4. Covalent modification of NIP45 by arginine methylation is an important mechanism of regulating the expression of NFAT-dependent cytokine genes.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Arginine / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cells, Cultured
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Cytokines / genetics
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Cytokines / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation*
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Humans
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Interferon-gamma / metabolism
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Interleukin-4 / metabolism
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Intracellular Signaling Peptides and Proteins*
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Methylation
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Mice
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Mice, Inbred BALB C
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Molecular Sequence Data
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NFATC Transcription Factors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein-Arginine N-Methyltransferases / genetics
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Protein-Arginine N-Methyltransferases / metabolism*
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Receptors, Antigen, T-Cell / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / physiology*
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Carrier Proteins
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Cytokines
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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NFATC Transcription Factors
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Nfatc2ip protein, mouse
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Nuclear Proteins
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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Transcription Factors
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Interleukin-4
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Interferon-gamma
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Arginine
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Protein-Arginine N-Methyltransferases
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coactivator-associated arginine methyltransferase 1