The differential regulation of human ACT1 isoforms by Hsp90 in IL-17 signaling.
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.
Mesh Terms:
Alternative Splicing, Base Sequence, Binding Sites, Genetic Predisposition to Disease, HEK293 Cells, HSP90 Heat-Shock Proteins, HeLa Cells, Humans, Interleukin-17, Interleukins, Molecular Sequence Data, Mutation, Missense, Polymorphism, Single Nucleotide, Protein Isoforms, Psoriasis, RNA Interference, Signal Transduction, Skin, Th17 Cells, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Alternative Splicing, Base Sequence, Binding Sites, Genetic Predisposition to Disease, HEK293 Cells, HSP90 Heat-Shock Proteins, HeLa Cells, Humans, Interleukin-17, Interleukins, Molecular Sequence Data, Mutation, Missense, Polymorphism, Single Nucleotide, Protein Isoforms, Psoriasis, RNA Interference, Signal Transduction, Skin, Th17 Cells, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
J. Immunol.
Date: Aug. 15, 2014
PubMed ID: 25024377
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