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

Nature Immunology volume 14, pages 72–81 (2013)Cite this article

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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 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.

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Figure 1: Act1 is a client protein of hsp90.
Figure 2: The activity of hsp90 is required for IL-17-induced, Act1-mediated signaling.
Figure 3: Loss of interaction of Act1(D10N) with hsp90.
Figure 4: The IL-17-induced Act1-hsp90 interaction is TRAF6 independent.
Figure 5: Act1(D10N) is a loss-of-function variant of Act1.
Figure 6: Neutralization of IL-22 attenuates skin inflammation in Act1−/− mice.
Figure 7: Skin inflammation is attenuated in Act1−/− Il23r−/− mice.
Figure 8: Skin inflammation in mice with T cell–specific deletion of Act1.

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Acknowledgements

We thank AML Laboratories and the Lerner Research Institute Histology Core for processing tissue samples for histology; J. Ma and W. Qian for technical support; and N. Volokh and D. Kish for discussions. Supported by the US National Institutes of Health (1R01NS071996 and 1P01 HL103453 to X.L.; and T32 GM007250 to the Case Western Reserve University Medical Scientist Training Program and T32 AI 89474-1 to the Case Western Reserve University Immunology Training Program, for support of L.W.) and the American Asthma Foundation (X.L.).

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  1. Chenhui Wang and Ling Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Chenhui Wang, Ling Wu, Katarzyna Bulek, Bradley N Martin, Jarod A Zepp, Zizhen Kang, Caini Liu, Tomasz Herjan & Xiaoxia Li

  2. Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA

    Ling Wu & Bradley N Martin

  3. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Saurav Misra

  4. Discovery Biology, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Julie A Carman, Ji Gao & Ashok Dongre

  5. Aflac Cancer & Blood Disorders Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA

    Shujie Han & Kevin D Bunting

  6. Department of Anatomic Pathology & Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Jennifer S Ko

  7. Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

    Hui Xiao

  8. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Vijay K Kuchroo

  9. Department of Immunology, Genentech, South San Francisco, California, USA

    Wenjun Ouyang

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Contributions

C.W. and L.W. did the experiments and analyzed the data; K.B., J.A.Z., B.N.M., T.H., Z.K. and H.X. contributed to the experiments; C.L. provided constructs; J.A.C., A.D. and J.G. were part of the collaborative team at Bristol-Myers Squibb that analyzed the mass spectrometry data; S.H. and K.D.B. contributed retroviral stock; J.S.K. provided clinical expertise; V.K.K. and W.O. provided reagents; L.W., C.W. and X.L. wrote the manuscript; and L.W., S.M., J.A.Z., K.D.B. and X.L. edited the paper.

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Correspondence to Xiaoxia Li.

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Competing interests

J.A.C., J.G. and A.D. are employees of Bristol-Meyers-Squibb; W.O. is an employee of Genentech.

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Wang, C., Wu, L., Bulek, K. et al. The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90. Nat Immunol 14, 72–81 (2013). https://doi.org/10.1038/ni.2479

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