title: The differential regulation of human ACT1 isoforms by Hsp90 in IL-17 signaling.
abstract: IL-17 is a proinflammatory cytokine implicated in the pathogenesis of autoimmune diseases including psoriasis. ACT1 is an essential adaptor molecule in the IL-17 signaling pathway. A missense single nucleotide polymorphism (rs33980500; SNP-D10N) that resulted in the substitution of an asparagine for an aspartic acid at position 10 of ACT1 (ACT1-D10N) is associated with psoriasis susceptibility. Due to alternative splicing in humans, SNP-D10N encodes two mutated ACT1 proteins, ACT1-D10N and ACT1-D19N. Although both ACT1 isoforms are Hsp90 client proteins, the nine additional amino acids in ACT1-D19N provide an additional Hsp90 binding site that is absent in ACT1-D10N. Therefore, whereas ACT1-D10N is a dead protein that is unable to transduce IL-17 signals for gene expression, ACT1-D19N is fully responsive to IL-17. Intriguingly, the two ACT1 isoforms are differentially expressed in ACT1(D10N/D10N) fibroblasts and T cells. Fibroblasts express both isoforms equally, enabling ACT1-D19N to compensate for the loss of ACT1-D10N function. ACT1(D10N/D10N) T cells, however, express predominantly ACT1-D10N. Lacking this compensatory mechanism, ACT1(D10N/D10N) T cells behave like ACT1-deficient T cells, exhibiting a dysregulated and hyperactive Th17 phenotype with overproduction of IL-22 and IL-17. The hyperactive Th17 response combined with fully responsive fibroblasts likely synergized to contribute to psoriasis susceptibility in SNP-D10N patients.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195;
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195;
authors.forename: Chenhui
authors.initials: C
authors.lastname: Wang
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195;
authors.forename: Saurav
authors.initials: S
authors.lastname: Misra
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195;
authors.forename: Patricia
authors.initials: P
authors.lastname: Rayman
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195;
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; INSERM Unité Mixte de Recherche 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris 75015, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris 75015, France; and.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; INSERM Unité Mixte de Recherche 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris 75015, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris 75015, France; and Pediatric Hematology-Immunology Unit, Necker Hospital, Paris 75015, France lix@ccf.org casanova@mail.rockefeller.edu.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; lix@ccf.org casanova@mail.rockefeller.edu.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction / Q000276:immunology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D000097043:Interleukin-22
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018841:HSP90 Heat-Shock Proteins; D020381:Interleukin-17; D007378:Interleukins; D020033:Protein Isoforms; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000097043:Interleukin-22; C414202:TRAF3IP2 protein, human