AbstractsBiology & Animal Science

IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of autoimmune diseases including psoriasis. ACT1 is an essential adaptor molecule in the IL-17 signaling pathway. Here we found that ACT1 is a client protein of the molecular chaperone Hsp90. 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. We demonstrated that ACT1-D10N was defective in its interaction with hsp90, which resulted in a global loss of ACT1 function. Act1-deficient mice modeled the mechanistic link between loss of Act1 function and susceptibility to psoriasis. Although Act1 was necessary for IL-17-mediated inflammation, Act1-deficient mice had a hyperactive response of the Th17 subset of helper T cells and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17-signaling, IL-22 was the main contributor to skin inflammation. Due to alternative splicing in humans, however, SNP-D10N encodes two mutated ACT1 proteins, ACT1-D10N and ACT1-D19N. Though 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, while 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 ACT1D10N/D10N fibroblasts and T cells. Fibroblasts express both isoforms equally, enabling ACT1-D19N to compensate for the loss of ACT1-D10N function. ACT1D10N/D10N T cells, however, express predominantly ACT1-D10N. Lacking this compensatory mechanism, ACT1D10N/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.