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A HYPER TH17 RESPONSE CONNECTS THE PSORIASIS-ASSOCIATED ACT1 VARIANT TO SKIN INFLAMMATION

Wu, Ling
http://rave.ohiolink.edu/etdc/view?acc_num=case1409866338

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Pathology.
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.
George Dubyak, PhD (Committee Chair)
Clive Hamlin, PhD (Committee Member)
Alex Huang, MD/PhD (Committee Member)
Derek Abbott, MD/PhD (Committee Member)
Xiaoxia Li, PhD (Advisor)
163 p.
Biochemistry; Cellular Biology; Health Sciences; Immunology
IL-17; Act1; Traf3ip2; psoriasis

Recommended Citations

Citations

  • Wu, L. (2015). A HYPER TH17 RESPONSE CONNECTS THE PSORIASIS-ASSOCIATED ACT1 VARIANT TO SKIN INFLAMMATION [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1409866338

    APA Style (7th edition)

  • Wu, Ling. A HYPER TH17 RESPONSE CONNECTS THE PSORIASIS-ASSOCIATED ACT1 VARIANT TO SKIN INFLAMMATION. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1409866338.

    MLA Style (8th edition)

  • Wu, Ling. "A HYPER TH17 RESPONSE CONNECTS THE PSORIASIS-ASSOCIATED ACT1 VARIANT TO SKIN INFLAMMATION." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1409866338

    Chicago Manual of Style (17th edition)

case1409866338
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© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.