1. An ACT1 Mutation Selectively Abolishes Interleukin-17 Responses in Humans with Chronic Mucocutaneous Candidiasis
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Michel Rybojad, Vincent Pedergnana, Bertrand Boisson, Jean-Laurent Casanova, Ling Wu, Claire Fieschi, Laurent Abel, Capucine Picard, Xiaoxia Li, Aziz Belkadi, Chenhui Wang, Sophie Cypowyj, Anne Puel, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Cleveland Clinic, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Université Paris Diderot - Paris 7 (UPD7), and Herrada, Anthony
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Male ,T-Lymphocytes ,MESH: Interleukin-17 ,[SDV]Life Sciences [q-bio] ,MESH: Amino Acid Sequence ,MESH: Heat-Shock Proteins ,medicine.disease_cause ,MESH: Receptors, Interleukin-17 ,MESH: Protein Structure, Tertiary ,0302 clinical medicine ,MESH: CD40 Antigens ,Immunology and Allergy ,Missense mutation ,Chronic mucocutaneous candidiasis ,MESH: Candidiasis, Chronic Mucocutaneous ,Receptor ,Heat-Shock Proteins ,0303 health sciences ,Mutation ,Receptors, Interleukin-17 ,MESH: Protein Multimerization ,Candidiasis, Chronic Mucocutaneous ,Homozygote ,Interleukin-17 ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,Pedigree ,[SDV] Life Sciences [q-bio] ,Infectious Diseases ,Female ,Tumor necrosis factor alpha ,MESH: Immunity, Innate ,Interleukin 17 ,MESH: Homozygote ,Adult ,MESH: Pedigree ,Molecular Sequence Data ,Immunology ,Mucocutaneous zone ,Mutation, Missense ,macromolecular substances ,Biology ,MESH: Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,Article ,03 medical and health sciences ,Heat shock protein ,medicine ,Humans ,Amino Acid Sequence ,CD40 Antigens ,Immunity, Mucosal ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,MESH: Adaptor Proteins, Signal Transducing ,MESH: Mutation, Missense ,MESH: Molecular Sequence Data ,MESH: Humans ,Siblings ,MESH: Adult ,Fibroblasts ,medicine.disease ,Immunity, Innate ,MESH: Male ,Protein Structure, Tertiary ,MESH: Siblings ,MESH: T-Lymphocytes ,MESH: Fibroblasts ,MESH: Immunity, Mucosal ,Protein Multimerization ,MESH: Female ,030215 immunology - Abstract
International audience; 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.
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