An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis

Immunity. 2013 Oct 17;39(4):676-86. doi: 10.1016/j.immuni.2013.09.002. Epub 2013 Oct 10.


Patients with inborn errors of interleukin-17F (IL-17F) or IL-17RA display chronic mucocutaneous candidiasis (CMC). We report a biallelic missense mutation (T536I) in the adaptor molecule ACT1 in two siblings with CMC. The mutation, located in the SEFIR domain, abolished the homotypic interaction of ACT1 with IL-17 receptors, with no effect on homodimerization. The patients' fibroblasts failed to respond to IL-17A and IL-17F, and their T cells to IL-17E. By contrast, healthy individuals homozygous for the common variant D10N, located in the ACT1 tumor necrosis factor receptor-associated factor-interacting domain and previously associated with psoriasis, had impaired, but not abolished, responses to IL-17 cytokines. SEFIR-independent interactions of ACT1 with other proteins, such as CD40, heat shock protein 70 (HSP70) and HSP90, were not affected by the T536I mutation. Overall, human IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity. Moreover, other ACT1-dependent IL-17 cytokines seem to be largely redundant in host defense.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Amino Acid Sequence
  • CD40 Antigens / genetics
  • CD40 Antigens / immunology
  • Candidiasis, Chronic Mucocutaneous / genetics*
  • Candidiasis, Chronic Mucocutaneous / immunology
  • Candidiasis, Chronic Mucocutaneous / pathology
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / pathology
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / immunology
  • Homozygote
  • Humans
  • Immunity, Innate
  • Immunity, Mucosal
  • Interleukin-17 / genetics*
  • Interleukin-17 / immunology
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Receptors, Interleukin-17 / genetics*
  • Receptors, Interleukin-17 / immunology
  • Siblings
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics*
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / immunology


  • Adaptor Proteins, Signal Transducing
  • CD40 Antigens
  • Heat-Shock Proteins
  • IL17A protein, human
  • IL17F protein, human
  • IL25 protein, human
  • Interleukin-17
  • Receptors, Interleukin-17
  • TRAF3IP2 protein, human
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins