Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity

Cell Host Microbe. 2014 Apr 9;15(4):494-505. doi: 10.1016/j.chom.2014.03.008.


Recognition of fungal pathogens by C-type lectin receptor (CLR) dectin-1 on human dendritic cells is essential for triggering protective antifungal TH1 and TH17 immune responses. We show that Fonsecaea monophora, a causative agent of chromoblastomycosis, a chronic fungal skin infection, evades these antifungal responses by engaging CLR mincle and suppressing IL-12, which drives TH1 differentiation. Dectin-1 triggering by F. monophora activates transcription factor IRF1, which is crucial for IL12A transcription via nucleosome remodeling. However, simultaneous F. monophora binding to mincle induces an E3 ubiquitin ligase Mdm2-dependent degradation pathway, via Syk-CARD9-mediated PKB signaling, that leads to loss of nuclear IRF1 activity, hence blocking IL12A transcription. The absence of IL-12 leads to impaired TH1 responses and promotes TH2 polarization. Notably, mincle is similarly exploited by other chromoblastomycosis-associated fungi to redirect TH responses. Thus, mincle is a fungal receptor that can suppress antifungal immunity and, as such, is a potential therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CARD Signaling Adaptor Proteins / immunology
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Chromoblastomycosis / immunology
  • Dendritic Cells / immunology
  • Humans
  • Interferon Regulatory Factor-1 / biosynthesis
  • Interferon Regulatory Factor-1 / genetics
  • Interleukin-12 Subunit p35 / biosynthesis*
  • Interleukin-12 Subunit p35 / genetics
  • Interleukin-12 Subunit p35 / immunology
  • Intracellular Signaling Peptides and Proteins / immunology
  • Lectins, C-Type / immunology*
  • Protein-Tyrosine Kinases / immunology
  • Proto-Oncogene Proteins c-mdm2 / immunology
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Immunologic / immunology*
  • Saccharomycetales / immunology*
  • Syk Kinase
  • Th1 Cells / immunology
  • Th17 Cells / immunology


  • CARD Signaling Adaptor Proteins
  • CARD9 protein, human
  • CLEC4D protein, human
  • IL12A protein, human
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Interleukin-12 Subunit p35
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • RNA, Small Interfering
  • Receptors, Immunologic
  • dectin 1
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase