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

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.
Mesh Terms:
Adult, Amino Acid Sequence, Antigens, CD40, Candidiasis, Chronic Mucocutaneous, Female, Fibroblasts, Heat-Shock Proteins, Homozygote, Humans, Immunity, Innate, Immunity, Mucosal, Interleukin-17, Male, Molecular Sequence Data, Mutation, Missense, Pedigree, Protein Multimerization, Protein Structure, Tertiary, Receptors, Interleukin-17, Siblings, T-Lymphocytes, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Immunity
Date: Oct. 17, 2013
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