Publication: Psoriasis-associated variant Act1 D10N with impaired regulation by Hsp90
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2012
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Wang, C., L. Wu, K. Bulek, B. N. Martin, J. A. Zepp, Z. Kang, C. Liu, et al. 2012. “Psoriasis-associated variant Act1 D10N with impaired regulation by Hsp90.” Nature immunology 14 (1): 72-81. doi:10.1038/ni.2479. http://dx.doi.org/10.1038/ni.2479.
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Abstract
Act1 is an essential adaptor molecule in IL-17-mediated signaling and is recruited to the IL-17 receptor upon IL-17 stimulation. Here, we report that Act1 is a client protein of the molecular chaperone, Hsp90. The Act1 variant (D10N) linked to psoriasis susceptibility is defective in its interaction with Hsp90, resulting in a global loss of Act1 function. Act1-/- mice modeled the mechanistic link between Act1 loss of function and psoriasis susceptibility. Although Act1 is necessary for IL-17-mediated inflammation, Act1-/- mice exhibited a hyper TH17 response and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17-signaling, IL-22 is the main contributor to skin inflammation, providing a molecular mechanism for the association of Act1 (D10N) with psoriasis susceptibility.
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