GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT6-signaling to IgE production in B cells.
Antigen (Ag)-driven B cells undergo antibody (Ab) affinity maturation and class switching in germinal center (GC) B cells. GANP is one of the molecules required for Ab affinity maturation. We herein found an increase of IgE in B cell ganp-deficient mice and studied the signal transduction pathway regulated by GANP. GANP suppresses the STAT-mediated transcription activity in GC B cells with the regulation of arginine methyltransferase activity by the interaction with JAK-binding protein arginine methyltransferase (PRMT) 5 and JAK1/JAK3 that are responsible for STAT6 activation. The prmt5 mRNA was up-regulated in B cells after stimulation in vitro and in vivo in GC B cells. The loss of GANP caused up-regulation of phosphorylation and arginine dimethylation of STAT6 in B cells after stimulation with LPS and IL-4 in vitro. On the contrary, GANP over-expressed B cells in ganp gene-transgenic mice showed a low STAT6 phosphorylation after stimulation. The over-expression of PRMT5 caused the up-regulation of STAT6-mediated gene transcription, which was also suppressed by the co-transfection of GANP, in luciferase reporter assay. GANP down-regulates JAK1/JAK3 to STAT6-signaling with regulation of arginine methylation activity, which might be responsible for the B cell endogenous suppressive mechanism of hyper-IgE.
Igarashi
Hideya
H
Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto 860-8556, Japan.
Kuwahara
Kazuhiko
K
Yoshida
Mikoto
M
Xing
Yan
Y
Maeda
Kazuhiko
K
Nakajima
Koichi
K
Sakaguchi
Nobuo
N
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D053613:Janus Kinase 1 / Q000276:immunology / Q000378:metabolism; D053616:Janus Kinase 3 / Q000276:immunology / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases; D050800:STAT6 Transcription Factor / Q000276:immunology* / Q000502:physiology; D015398:Signal Transduction; D015854:Up-Regulation
C481510:GANP protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D007073:Immunoglobulin E; D011496:Protein Methyltransferases; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3