272 : The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone Hsp90

详细信息    查看全文

• 作者：Chenhui Wang ; Ling Wu ; Katarzyna Bulek ; Bradley N. Martin ; Jarod A. Zepp ; Zizhen Kang ; Caini Liu ; Tomasz Herjan ; Saurav Misra ; Julie A. Carman ; Ji Gao ; Ashok Dongre ; Shujie Han ; Kevin D. Bunting ; Jennifer S. Ko ; Hui Xiao ; Vijay K. Kuchroo ; Wenjun Ouyang ; Xiaoxia Li
• 刊名：Cytokine
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：63
• 期：3
• 页码：307
• 全文大小：42 K

文摘

Act1 is an essential adaptor in interleukin 17 (IL-17)-mediated signaling and is recruited to the receptor for IL-17 after stimulation with IL-17. Here we found that Act1 was a ¡®client¡¯ protein of the molecular chaperone hsp90. The D10N variant of Act1 (Act1(D10N)) that is linked to susceptibility to psoriasis 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, which provides a molecular mechanism for the association of Act1(D10N) with psoriasis susceptibility.