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 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.

References

  1. 1

    Lowes, M.A., Bowcock, A.M. & Krueger, J.G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Nickoloff, B.J. & Nestle, F.O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J. Clin. Invest. 113, 1664–1675 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Chan, J.R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J. Exp. Med. 203, 2577–2587 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  Article  Google Scholar 

  5. 5

    Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  6. 6

    Iwakura, Y. & Ishigame, H. The IL-23/IL-17 axis in inflammation. J. Clin. Invest. 116, 1218–1222 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ouyang, W. Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine Growth Factor Rev. 21, 435–441 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Res, P.C. et al. Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis. PLoS ONE 5, e14108 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Caruso, R. et al. Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat. Med. 15, 1013–1015 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Cho, J.S. et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J. Clin. Invest. 120, 1762–1773 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Conti, H.R. et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J. Exp. Med. 206, 299–311 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Chang, S.H., Park, H. & Dong, C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J. Biol. Chem. 281, 35603–35607 (2006).

    CAS  Google Scholar 

  14. 14

    Qian, Y. et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol. 8, 247–256 (2007).

    CAS  Google Scholar 

  15. 15

    Sonder, S.U. et al. IL-17-induced NF-κB activation via CIKS/Act1: physiologic significance and signaling mechanisms. J. Biol. Chem. 286, 12881–12890 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1240 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Liu, C. et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci. Signal. 2, ra63 (2009).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Kang, Z. et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32, 414–425 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Swaidani, S. et al. The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation. J. Immunol. 182, 1631–1640 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Qian, Y. et al. Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity 21, 575–587 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Matsushima, Y. et al. An atopic dermatitis-like skin disease with hyper-IgE-emia develops in mice carrying a spontaneous recessive point mutation in the Traf3ip2 (Act1/CIKS) gene. J. Immunol. 185, 2340–2349 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Strange, A. et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ellinghaus, E. et al. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat. Genet. 42, 991–995 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Huffmeier, U. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat. Genet. 42, 996–999 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Sun, D. et al. Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nat. Immunol. 12, 853–860 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Zhu, S. et al. Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling. J. Exp. Med. 207, 2647–2662 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Taipale, M., Jarosz, D.F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat. Rev. Mol. Cell Biol. 11, 515–528 (2010).

    Article  CAS  Google Scholar 

  28. 28

    Trepel, J., Mollapour, M., Giaccone, G. & Neckers, L. Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer 10, 537–549 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Cerchietti, L.C. et al. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nat. Med. 15, 1369–1376 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Marubayashi, S. et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J. Clin. Invest. 120, 3578–3593 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Orthwein, A. et al. Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90. J. Exp. Med. 207, 2751–2765 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Weigert, O. et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J. Exp. Med. 209, 259–273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Schulz, R. et al. Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression. J. Exp. Med. 209, 275–289 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Waza, M. et al. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat. Med. 11, 1088–1095 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. 35

    Bulek, K. et al. The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nat. Immunol. 12, 844–852 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Ho, A.W. et al. IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail. J. Immunol. 185, 1063–1070 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Ryzhakov, G., Blazek, K. & Udalova, I.A. Evolution of vertebrate immunity: sequence and functional analysis of the SEFIR domain family member Act1. J. Mol. Evol. 72, 521–530 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Liang, S.C. et al. IL-22 induces an acute-phase response. J. Immunol. 185, 5531–5538 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Guilloteau, K. et al. Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α recapitulates some features of psoriasis. J. Immunol. (2010).

  40. 40

    Hu, Y. et al. IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis. J. Immunol. 184, 4307–4316 (2010).

    Article  CAS  Google Scholar 

  41. 41

    Annunziato, F., Cosmi, L., Liotta, F., Maggi, E. & Romagnani, S. Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat. Rev. Rheumatol. 5, 325–331 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Ma, H.L. et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J. Clin. Invest. 118, 597–607 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Van Belle, A.B. et al. IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J. Immunol. 188, 462–469 (2012).

    Article  CAS  Google Scholar 

  45. 45

    Rizzo, H.L. et al. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J. Immunol. 186, 1495–1502 (2011).

    Article  CAS  Google Scholar 

  46. 46

    Li, L.F., Sujan, S.A., Yang, H. & Wang, W.H. Serum immunoglobulins in psoriatic erythroderma. Clin. Exp. Dermatol. 30, 125–127 (2005).

    Article  PubMed  Google Scholar 

  47. 47

    Saraceno, R., Scotto, G., Chiricozzi, A. & Chimenti, S. Urticaria associated with hyper-IgE in a patient with psoriasis undergoing treatment with efalizumab. Acta Derm. Venereol. 89, 412–413 (2009).

    Article  PubMed  Google Scholar 

  48. 48

    Li, X.L. et al. Unusual psoriasiform lesions in a patient with Hyper-IgE syndrome. J. Eur. Acad. Dermatol. Venereol. 21, 424–426 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Awasthi, A. et al. Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. J. Immunol. 182, 5904–5908 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Swaidani, S. et al. T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation. J. Immunol. 187, 3155–3164 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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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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