IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27038-5.html
   My bibliography  Save this article

Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation

Author

Listed:
  • Grigory Ryzhakov

    (University of Oxford, Kennedy Institute of Rheumatology
    Novartis Pharma AG, Novartis Campus)

  • Hannah Almuttaqi

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Alastair L. Corbin

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Dorothée L. Berthold

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Tariq Khoyratty

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Hayley L. Eames

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Samuel Bullers

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Claire Pearson

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Zhichao Ai

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Kristina Zec

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Sarah Bonham

    (University of Oxford)

  • Roman Fischer

    (University of Oxford)

  • Luke Jostins-Dean

    (University of Oxford, Kennedy Institute of Rheumatology)

  • Simon P. L. Travis

    (John Radcliffe Hospital)

  • Benedikt M. Kessler

    (University of Oxford)

  • Irina A. Udalova

    (University of Oxford, Kennedy Institute of Rheumatology)

Abstract

Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, and has a key pathogenic function in gut inflammation, but how IRF5 is modulated is still unclear. Having performed a kinase inhibitor library screening in macrophages, here we identify protein-tyrosine kinase 2-beta (PTK2B/PYK2) as a putative IRF5 kinase. PYK2-deficient macrophages display impaired endogenous IRF5 activation, leading to reduction of inflammatory gene expression. Meanwhile, a PYK2 inhibitor, defactinib, has a similar effect on IRF5 activation in vitro, and induces a transcriptomic signature in macrophages similar to that caused by IRF5 deficiency. Finally, defactinib reduces pro-inflammatory cytokines in human colon biopsies from patients with ulcerative colitis, as well as in a mouse colitis model. Our results thus implicate a function of PYK2 in regulating the inflammatory response in the gut via the IRF5 innate sensing pathway, thereby opening opportunities for related therapeutic interventions for inflammatory bowel diseases and other inflammatory conditions.

Suggested Citation

  • Grigory Ryzhakov & Hannah Almuttaqi & Alastair L. Corbin & Dorothée L. Berthold & Tariq Khoyratty & Hayley L. Eames & Samuel Bullers & Claire Pearson & Zhichao Ai & Kristina Zec & Sarah Bonham & Roman, 2021. "Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27038-5
    DOI: 10.1038/s41467-021-27038-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27038-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27038-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yun Zhao & Rachid Zagani & Sung-Moo Park & Naohiro Yoshida & Pankaj Shah & Hans-Christian Reinecker, 2019. "Microbial recognition by GEF-H1 controls IKKε mediated activation of IRF5," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Luke Jostins & Stephan Ripke & Rinse K. Weersma & Richard H. Duerr & Dermot P. McGovern & Ken Y. Hui & James C. Lee & L. Philip Schumm & Yashoda Sharma & Carl A. Anderson & Jonah Essers & Mitja Mitrov, 2012. "Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease," Nature, Nature, vol. 491(7422), pages 119-124, November.
    3. Akinori Takaoka & Hideyuki Yanai & Seiji Kondo & Gordon Duncan & Hideo Negishi & Tatsuaki Mizutani & Shin-ichi Kano & Kenya Honda & Yusuke Ohba & Tak W. Mak & Tadatsugu Taniguchi, 2005. "Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors," Nature, Nature, vol. 434(7030), pages 243-249, March.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Chao Yang & Mahesh Bachu & Yong Du & Caroline Brauner & Ruoxi Yuan & Marie Dominique Ah Kioon & Giancarlo Chesi & Franck J. Barrat & Lionel B. Ivashkiv, 2022. "CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Hung-Yu Chiang & Hsueh-Han Lu & Janaki N. Sudhakar & Yu-Wen Chen & Nien-Shin Shih & Yi-Ting Weng & Jr-Wen Shui, 2022. "IL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Kerstin Thriene & Karin B. Michels, 2023. "Human Gut Microbiota Plasticity throughout the Life Course," IJERPH, MDPI, vol. 20(2), pages 1-14, January.
    3. Zhao Wang & Qian Liang & Xinyi Qian & Bolang Hu & Zhanye Zheng & Jianhua Wang & Yuelin Hu & Zhengkai Bao & Ke Zhao & Yao Zhou & Xiangling Feng & Xianfu Yi & Jin Li & Jiandang Shi & Zhe Liu & Jihui Hao, 2023. "An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    4. Fan Li & Hui Wang & Yan-Qi Li & Yebo Gu & Xin-Ming Jia, 2023. "C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27038-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.