title: 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.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Electronic address: bebo283@rockefeller.edu.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.forename: Chenhui
authors.initials: C
authors.lastname: Wang
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Sophie
authors.initials: S
authors.lastname: Cypowyj
authors.forename: Michel
authors.initials: M
authors.lastname: Rybojad
authors.forename: Aziz
authors.initials: A
authors.lastname: Belkadi
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000595:Amino Acid Sequence; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D020381:Interleukin-17 / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D053722:Receptors, Interleukin-17 / Q000235:genetics* / Q000276:immunology; D035781:Siblings; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; D006360:Heat-Shock Proteins; C508717:IL17A protein, human; C440021:IL17F protein, human; C486701:IL25 protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins