NIP45 controls the magnitude of the type 2 T helper cell response.
Nuclear factor of activated T cell (NFAT) transcription factors are key regulators of gene transcription within immune cells. The NFAT-interacting protein, (NIP45), augments NFAT-driven IL-4 expression by a mechanism that relies on arginine methylation. To establish the function of NIP45 in vivo, we generated mice with a targeted deletion of the gene encoding this cofactor. NIP45-deficient T helper cells displayed profound defects in the expression of NFAT-regulated cytokine genes, including IL-4. Whereas NIP45 deficiency does not interfere with T helper cell NFAT activation or lineage-specific transcription-factor expression, NIP45 acts as an enhancer for the assembly of protein arginine methyltransferase 1 and the protein arginine methyltransferase 1-linked histone 4 arginine 3 methylation with the IL-4 promoter. Our study reveals an essential role for NIP45 in promoting robust cytokine expression in vivo, which is required for the efficient handling of parasites. We propose that NIP45 acts as a molecular rheostat serving to amplify the type-2 immune response.
Fathman
John W
JW
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Gurish
Michael F
MF
Hemmers
Saskia
S
Bonham
Kevin
K
Friend
Daniel S
DS
Grusby
Michael J
MJ
Glimcher
Laurie H
LH
Mowen
Kerri A
KA
D000818:Animals; D001120:Arginine / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D016207:Cytokines / Q000235:genetics*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D017160:Trichinella spiralis; D014235:Trichinellosis / Q000276:immunology
D016207:Cytokines; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; C102566:Nfatc2ip protein, mouse; D009687:Nuclear Proteins; D015847:Interleukin-4; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases