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

Abstract

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.

• Authors: Bertrand Boisson, Chenhui Wang, Vincent Pedergnana, Ling Wu, Sophie Cypowyj, Michel Rybojad, Aziz Belkadi, Capucine Picard, Laurent Abel, Claire Fieschi, Anne Puel, Xiaoxia Li, Jean-Laurent Casanova
• Journal: Immunity (Immunity) Vol. 39 Issue 4 Pg. 676-86 (Oct 17 2013) ISSN: 1097-4180 [Electronic] United States
• PMID: 24120361 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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