GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT6-signaling to IgE production in B cells

Mol Immunol. 2009 Mar;46(6):1031-41. doi: 10.1016/j.molimm.2008.08.272. Epub 2009 Feb 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism*
  • Cell Differentiation / physiology
  • Cell Line
  • Enzyme Activation
  • Humans
  • Immunoglobulin E / biosynthesis
  • Immunoglobulin E / immunology*
  • Interleukin-4 / immunology*
  • Janus Kinase 1 / immunology
  • Janus Kinase 1 / metabolism
  • Janus Kinase 3 / immunology
  • Janus Kinase 3 / metabolism
  • Methylation
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / immunology*
  • Nuclear Proteins / metabolism
  • Phosphoproteins / immunology*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Methyltransferases / antagonists & inhibitors
  • Protein Methyltransferases / immunology*
  • Protein Methyltransferases / metabolism
  • Protein-Arginine N-Methyltransferases
  • STAT6 Transcription Factor / immunology*
  • STAT6 Transcription Factor / physiology
  • Signal Transduction
  • Up-Regulation

Substances

  • GANP protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Interleukin-4
  • Immunoglobulin E
  • Protein Methyltransferases
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • Jak1 protein, mouse
  • Jak3 protein, mouse
  • Janus Kinase 1
  • Janus Kinase 3