title: The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90.
abstract: 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 T(H)17 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.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Martin
authors.forename: Jarod A
authors.initials: JA
authors.lastname: Zepp
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Kang
authors.forename: Caini
authors.initials: C
authors.lastname: Liu
authors.forename: Tomasz
authors.initials: T
authors.lastname: Herjan
authors.forename: Saurav
authors.initials: S
authors.lastname: Misra
authors.forename: Julie A
authors.initials: JA
authors.lastname: Carman
authors.forename: Ji
authors.initials: J
authors.lastname: Gao
authors.forename: Ashok
authors.initials: A
authors.lastname: Dongre
authors.forename: Shujie
authors.initials: S
authors.lastname: Han
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Ko
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011565:Psoriasis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C541130:ACT1 protein; D018031:Connexin 43; D018841:HSP90 Heat-Shock Proteins; D020381:Interleukin-17; D018832:Molecular Chaperones; D010446:Peptide Fragments