Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGFβ-activated kinase 1 (TAK1) play essential roles in the C-type lectin receptor signaling in response to Candida albicans infection

J Biol Chem. 2012 Dec 28;287(53):44143-50. doi: 10.1074/jbc.M112.414276. Epub 2012 Nov 12.

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGFβ-activated kinase 1 (TAK1) are considered as key intermediates in Toll-like receptor (TLR) signaling. However, the role of TRAF6 and TAK1 in C-type lectin receptors (CLRs) in response to fungal infection has not been studied. In this study, we have utilized macrophages derived from TRAF6 knock-out mice and myeloid-specific TAK1-deficient mice and determined the role of TRAF6 and TAK1 in CLR-induced signal transduction events. We demonstrate that TRAF6 and TAK1 are required for NF-κB and JNK activation, and expression of proinflammatory cytokines in response to Candida albicans infection. Our results highlight TRAF6 and TAK1 as key components in the signaling cascade downstream of C-type lectin receptors and as critical mediators of the anti-fungal immune response. Therefore, our studies provide a mechanistic understanding of the host immune response to C. albicans, which has a significant impact for the development of anti-fungal therapeutics and in understanding risk-factors and determining susceptibility to C. albicans infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Candida albicans / immunology
  • Candida albicans / physiology*
  • Candidiasis / enzymology
  • Candidiasis / genetics
  • Candidiasis / immunology*
  • Cells, Cultured
  • Female
  • Humans
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / immunology*
  • Macrophages / immunology
  • Macrophages / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology*

Substances

  • Lectins, C-Type
  • TNF Receptor-Associated Factor 6
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7