Wang, ChenhuiWu, LingBulek, KatarzynaMartin, Bradley N.Zepp, Jarod A.Kang, ZizhenLiu, CainiHerjan, TomaszMisra, SauravCarman, Julie A.Gao, JiDongre, AshokHan, ShujieBunting, Kevin D.Ko, Jennifer S.Xiao, HuiKuchroo, VijayOuyang, WenjunLi, Xiaoxia2014-02-182012Wang, 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.2479.1529-2908http://nrs.harvard.edu/urn-3:HUL.InstRepos:11717648Act1 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.en-USJournal Article2014-02-1810.1038/ni.2479