TRAF6 Negatively Regulates the Jak1-Erk Pathway in interleukin-2 Signaling

Genes Cells. 2011 Feb;16(2):179-89. doi: 10.1111/j.1365-2443.2010.01474.x. Epub 2010 Dec 13.

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a critical role in establishing both innate and acquired immune responses by mediating signals from the TNF superfamily, the TLR/IL-1R family, and the T-cell receptor. Here, we report a previously unidentified function of TRAF6 in IL-2 signaling. CD3/CD28 stimulation-induced proliferation and Il2 mRNA expression in Traf6(-/-) CD4(+) T cells were dramatically enhanced. This enhancement is likely due to hyperactive IL-2 signaling, in which activation of the Jak1-Erk pathway was enhanced and the subsequent Fos gene expression was up-regulated. To elucidate the molecular mechanisms of the enhanced activation of Jak1, IL-2 signaling was reconstituted in mouse embryonic fibroblast (MEF) cells to investigate the interaction between TRAF6 and the TRAF6-binding site that overlaps with the Jak1-binding site present in the IL-2R β-chain. The Jak1-Erk pathway was activated upon IL-2 stimulation in Traf6(-/-) MEF cells, while a β-chain mutation that inactivates TRAF6 binding but retains Jak1 binding abrogated the TRAF6-dependent reduction in IL-2 signaling. These results indicate that the binding of TRAF6 to the TRAF6-binding site of the β-chain negatively regulates IL-2-induced Jak1 activation, which is likely to be involved in the proper regulation of T-cell activation and development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Transfer Techniques
  • HEK293 Cells
  • Humans
  • Interleukin-2 / metabolism*
  • Interleukin-2 Receptor beta Subunit / metabolism*
  • Janus Kinase 1 / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Mutant Strains
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Up-Regulation

Substances

  • Interleukin-2
  • Interleukin-2 Receptor beta Subunit
  • Receptors, Antigen, T-Cell
  • TNF Receptor-Associated Factor 6
  • Jak1 protein, mouse
  • Janus Kinase 1
  • Extracellular Signal-Regulated MAP Kinases