Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The Act1 D10N missense variant impairs CD40 signaling in human B-cells

Genes & Immunity volume 20, pages 23–31 (2019)Cite this article

Subjects

Abstract

The TRAF3IP2 gene resides within one of at least 63 psoriasis susceptibility loci and encodes Act1, an adapter protein involved in IL-17 receptor and CD40 signaling pathways. TRAF3IP2 is distinctive (among <10% of candidate susceptibility genes) in that a strongly disease-associated variant encodes a missense SNP predicted to be functionally relevant (SNP rs33980500 C/T encoding Act1 pD10N). As assessed by flow cytometry, Act1 protein was expressed at the highest levels in monocytes, with lower levels in T-cells and B-cells. However, monocytes, T-cells and B-cells failed to respond to IL-17A stimulation of PBMC, as measured by flow cytometric determination of NF-κB phospho-p65. As an alternative stimulus, we treated PBMCs with trimerized recombinant human CD40L and assessed p65, p38 and Erk phosphorylation in CD19+ B-cells as a function of D10N genotype. The increase of phosphorylated p65, p38, and Erk was well-correlated across individuals, and CD40L-induced phosphorylation of p65, p38, and Erk was significantly attenuated in B-cells from Act1 D10N homozygotes, compared to heterozygotes and nullizygotes. Our results indicate that the Act1 D10N variant is a relevant genetic determinant of CD40L responsiveness in human B-cells, with the risk allele being associated with lower B-cell responses in an acute signaling context.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gudjonsson JE, Elder JT. Psoriasis. In: Goldsmith L, Katz SI, Gilchrest BA, Paller AS, Woolf K, Leffell DJ, editors. Dermatology in general medicine. 8th edn; Vol. 1. New York: McGraw-Hill; 2012. p. 197–231.

    Google Scholar 

  2. Kim J, Krueger JG. The immunopathogenesis of psoriasis. Dermatol Clin. 2015;33:13–23.

    Article  CAS  Google Scholar 

  3. Martin DA, Towne JE, Kricorian G, Klekotka P, Gudjonsson JE, Krueger JG, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol. 2013;133:17–26.

    Article  CAS  Google Scholar 

  4. Johansen C, Usher PA, Kjellerup RB, Lundsgaard D, Iversen L, Kragballe K. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009;160: 319–24.

    Article  CAS  Google Scholar 

  5. Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I, Nograles KE, et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol. 2008;181:7420–7.

    Article  CAS  Google Scholar 

  6. Johnston A, Fritz Y, Dawes SM, Diaconu D, Al-Attar PM, Guzman AM, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. J Immunol. 2013;190:2252–62.

    Article  CAS  Google Scholar 

  7. Chang SH, Park H, Dong C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem. 2006;281:35603–7.

    Article  CAS  Google Scholar 

  8. Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol. 2007;8:247–56.

    Article  CAS  Google Scholar 

  9. Sonder SU, Saret S, Tang W, Sturdevant DE, Porcella SF, Siebenlist U. IL-17-induced NF-kappaB activation via CIKS/Act1: physiologic significance and signaling mechanisms. J Biol Chem. 2011;286:12881–90.

    Article  CAS  Google Scholar 

  10. Liu C, Qian W, Qian Y, Giltiay NV, Lu Y, Swaidani S, et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal. 2009;2:ra63.

    PubMed  PubMed Central  Google Scholar 

  11. Luo Q, Sun Y, Liu W, Qian C, Jin B, Tao F, et al. A novel disease-modifying antirheumatic drug, iguratimod, ameliorates murine arthritis by blocking IL-17 signaling, distinct from methotrexate and leflunomide. J Immunol. 2013;191:4969–78.

    Article  CAS  Google Scholar 

  12. Qian Y, Qin J, Cui G, Naramura M, Snow EC, Ware CF, et al. Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity. 2004;21:575–87.

    Article  CAS  Google Scholar 

  13. Edwards SL, Beesley J, French JD, Dunning AM. Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet. 2013;93:779–97.

    Article  CAS  Google Scholar 

  14. Ellinghaus E, Ellinghaus D, Stuart PE, Nair RP, Debrus S, Raelson JV, et al. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat Genet. 2010;42:991–5.

    Article  CAS  Google Scholar 

  15. Huffmeier U, Uebe S, Ekici AB, Bowes J, Giardina E, Korendowych E, et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet. 2010;42:996–9.

    Article  Google Scholar 

  16. Genetic Analysis of Psoriasis C, the Wellcome Trust Case Control C, Strange A, Capon F, Spencer CC, Knight J, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42:985–90.

    Article  Google Scholar 

  17. Stuart PE, Nair RP, Tsoi LC, Tejasvi T, Das S, Kang HM, et al. Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am J Hum Genet. 2015;97:816–36.

    Article  CAS  Google Scholar 

  18. Ghosh S, Hayden MS. Celebrating 25 years of NF-kappaB research. Immunol Rev. 2012;246:5–13.

    Article  Google Scholar 

  19. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009;9:556–67.

    Article  CAS  Google Scholar 

  20. Hayden MS, Ghosh S. Regulation of NF-kappaB by TNF family cytokines. Semin Immunol. 2014;26:253–66.

    Article  CAS  Google Scholar 

  21. Giltiay NV, Lu Y, Cullen JL, Jorgensen TN, Shlomchik MJ, Li X. Spontaneous loss of tolerance of autoreactive B cells in Act1-deficient rheumatoid factor transgenic mice. J Immunol. 2013;191:2155–63.

    Article  CAS  Google Scholar 

  22. Claudio E, Sonder SU, Saret S, Carvalho G, Ramalingam TR, Wynn TA, et al. The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J Immunol. 2009;182:1617–30.

    Article  CAS  Google Scholar 

  23. Craxton A, Shu G, Graves JD, Saklatvala J, Krebs EG, Clark EA. p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes. J Immunol. 1998;161: 3225–36.

    CAS  PubMed  Google Scholar 

  24. Li YY, Baccam M, Waters SB, Pessin JE, Bishop GA, Koretzky GA. CD40 ligation results in protein kinase C-independent activation of ERK and JNK in resting murine splenic B cells. J Immunol. 1996;157:1440–7.

    CAS  PubMed  Google Scholar 

  25. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009;41:199–204.

    Article  CAS  Google Scholar 

  26. Tsoi LC, Spain SL, Ellinghaus E, Stuart PE, Capon F, Knight J, et al. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci. Nat Commun. 2015;6:7001.

    Article  CAS  Google Scholar 

  27. Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44:1341–8.

    Article  CAS  Google Scholar 

  28. Wang C, Wu L, Bulek K, Martin BN, Zepp JA, Kang Z, et al. The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90. Nat Immunol. 2013;14:72–81.

    Article  CAS  Google Scholar 

  29. Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S, Rybojad M, et al. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity. 2013;39:676–86.

    Article  CAS  Google Scholar 

  30. Shahrara S, Pickens SR, Mandelin AM 2nd, Karpus WJ, Huang Q, Kolls JK, et al. IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction. J Immunol. 2010;184:4479–87.

    Article  CAS  Google Scholar 

  31. Wang CQF, Suárez-Fariñas M, Nograles KE, Mimoso CA, Shrom D, Dow ER, Heffernan MP, Hoffman RW, Krueger JG, IL-17 induces inflammation-associated gene products in blood monocytes, and treatment with ixekizumab reduces their expression in psoriasis patient blood. J Invest Dermatol. 2014;134:2990–3.

    Article  CAS  Google Scholar 

  32. Kehry MR. CD40-mediated signaling in B cells. Balancing cell survival, growth, and death. J Immunol. 1996;156:2345–8.

    CAS  PubMed  Google Scholar 

  33. Wennhold K, Shimabukuro-Vornhagen A, Theurich S, von Bergwelt-Baildon M. CD40-activated B cells as antigen-presenting cells: the final sprint toward clinical application. Expert Rev Vaccin. 2013;12:631–7.

    Article  CAS  Google Scholar 

  34. Hobeika E, Nielsen PJ, Medgyesi D. Signaling mechanisms regulating B-lymphocyte activation and tolerance. J Mol Med (Berl). 2015;93:143–58.

    Article  CAS  Google Scholar 

  35. Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M, Kountikov EI, et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature. 2012;491:264–8.

    Article  CAS  Google Scholar 

  36. Yang M, Rui K, Wang S, Lu L. Regulatory B cells in autoimmune diseases. Cell Mol Immunol. 2013;10:122–32.

    Article  Google Scholar 

  37. Hilgenberg E, Shen P, Dang VD, Ries S, Sakwa I, Fillatreau S. Interleukin-10-producing B cells and the regulation of immunity. Curr Top Microbiol Immunol. 2014;380:69–92.

    CAS  PubMed  Google Scholar 

  38. Austin ED, Rock MT, Mosse CA, Vnencak-Jones CL, Yoder SM, Robbins IM, et al. T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension. Respir Med. 2010;104:454–62.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the volunteers who provided blood samples for this study, and Dr. Andrew Johnston for advice on flow cytometry. This research was supported by National Institutes of Health (NIH) R01 grants AR042742, AR050511, AR054966, AR062382, and AR065183 to JTE. We also acknowledge generous support from the Dawn and Dudley Holmes Memorial Fund and the Babcock Endowment Fund to the Department of Dermatology at the University of Michigan. JTE is supported by the Ann Arbor Veterans Affairs Hospital.

Author information

Author notes

  1. Ning Yu and Sylviane Lambert contributed equally to this work

Authors and Affiliations

  1. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA

    Ning Yu, Sylviane Lambert, Joshua Bornstein, Rajan P. Nair, Charlotta Enerbäck & James T. Elder

  2. Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China

    Ning Yu

  3. Department of Dermatology, Linköping University, Linköping, Sweden

    Charlotta Enerbäck

  4. Ann Arbor Veterans Affairs Health System, Ann Arbor, MI, USA

    James T. Elder

Authors
  1. Ning Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylviane Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joshua Bornstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rajan P. Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charlotta Enerbäck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James T. Elder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ning Yu or James T. Elder.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, N., Lambert, S., Bornstein, J. et al. The Act1 D10N missense variant impairs CD40 signaling in human B-cells. Genes Immun 20, 23–31 (2019). https://doi.org/10.1038/s41435-017-0007-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-017-0007-7

Search

Advanced search

Quick links