The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90

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

doi:10.1038/ni.2479

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The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90

Journal article

Open access

Peer reviewed

The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90

Chenhui Wang, Ling Wu, Katarzyna Bulek, Bradley N Martin, Jarod A Zepp, Zizhen Kang, Caini Liu, Tomasz Herjan, Saurav Misra, Julie A Carman, …

Nature immunology, Vol.14(1), pp.72-81

01/2013

DOI: 10.1038/ni.2479

PMCID: PMC3522792

PMID: 23202271

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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.

Animals

Cell Line

Connexin 43 - genetics

Connexin 43 - immunology

Connexin 43 - metabolism

Disease Models, Animal

Genetic Predisposition to Disease

HSP90 Heat-Shock Proteins - metabolism

Humans

Interleukin-17 - metabolism

Mice

Mice, Knockout

Molecular Chaperones - genetics

Molecular Chaperones - metabolism

Mutation - genetics

Peptide Fragments - genetics

Peptide Fragments - immunology

Peptide Fragments - metabolism

Polymorphism, Genetic

Protein Binding - genetics

Protein Binding - immunology

Psoriasis - genetics

Psoriasis - immunology

Signal Transduction

Th17 Cells - immunology

Details

Title: Subtitle: The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90
Creators: Chenhui Wang - Cleveland Clinic
Ling Wu - Case Western Reserve University
Katarzyna Bulek - Cleveland Clinic
Bradley N Martin - Case Western Reserve University
Jarod A Zepp - Cleveland Clinic
Zizhen Kang - Cleveland Clinic
Caini Liu - Cleveland Clinic
Tomasz Herjan - Cleveland Clinic
Saurav Misra - Cleveland Clinic
Julie A Carman - Bristol-Myers Squibb
Ji Gao
Ashok Dongre - Bristol-Myers Squibb
Shujie Han - Emory University
Kevin D Bunting - Emory University
Jennifer S Ko - Cleveland Clinic
Hui Xiao - Chinese Academy of Sciences
Vijay K Kuchroo - Brigham and Women's Hospital
Wenjun Ouyang - Genentech
Xiaoxia Li - Cleveland Clinic
Resource Type: Journal article
Publication Details: Nature immunology, Vol.14(1), pp.72-81
DOI: 10.1038/ni.2479
PMID: 23202271
PMCID: PMC3522792
NLM abbreviation: Nat Immunol
ISSN: 1529-2908
eISSN: 1529-2916
Grant note: T32 AI89474-1 / NIAID NIH HHS P01 HL103453 / NHLBI NIH HHS T32 GM007250 / NIGMS NIH HHS 1R01NS071996 / NINDS NIH HHS UL1 TR000439 / NCATS NIH HHS 1P01 HL103453 / NHLBI NIH HHS R01 NS071996 / NINDS NIH HHS U10 HL109250 / NHLBI NIH HHS T32 AI089474 / NIAID NIH HHS T32 GM088088 / NIGMS NIH HHS R01 DK059380 / NIDDK NIH HHS R01 GM080271 / NIGMS NIH HHS
Language: English
Date published: 01/2013
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9984201122002771

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