Bruton's tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response

  • Cell Rep. 2015 Feb 24;10(7):1055-65. doi: 10.1016/j.celrep.2015.01.039.
Koon-Guan Lee  1 ,  Susana Soo-Yeon Kim  1 ,  Lin Kui  1 ,  Dominic Chih-Cheng Voon  2 ,  Marjorie Mauduit  3 ,  Pradeep Bist  4 ,  Xuezhi Bi  1 ,  Natasha Ann Pereira  1 ,  Chengcheng Liu  1 ,  Bindu Sukumaran  4 ,  Laurent Rénia  3 ,  Yoshiaki Ito  2 ,  Kong-Peng Lam  5
Affiliations
  • 1. Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
  • 2. Cancer Biology Program, Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
  • 3. Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.
  • 4. Emerging Infectious Diseases Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore.
  • 5. Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore; Departments of Microbiology, Physiology, and Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117574, Singapore. Electronic address: [email protected].
PMID: 25704810 DOI: 10.1016/j.celrep.2015.01.039
Abstract

The innate immune system senses cytosolic dsDNA and bacterial Cyclic Dinucleotides and initiates signaling via the adaptor STING to induce type 1 interferon (IFN) response. We demonstrate here that BTK-deficient cells have impaired IFN-β production and TBK1/IRF3 activation when stimulated with agonists or infected with pathogens that activate STING signaling. Btk interacts with STING and DDX41 helicase. The kinase and SH3/SH2 interaction domains of Btk bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. Btk phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the Btk phosphorylation site. Modeling studies further indicate that phospho-Tyr414 strengthens DDX41's interaction with STING. Hence, Btk plays a critical role in the activation of DDX41 helicase and STING signaling.