title: Bruton's tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response.
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.
authors.affiliation: Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
authors.forename: Koon-Guan
authors.initials: KG
authors.lastname: Lee
authors.affiliation: Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
authors.forename: Susana Soo-Yeon
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
authors.forename: Lin
authors.initials: L
authors.lastname: Kui
authors.affiliation: Cancer Biology Program, Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Dominic Chih-Cheng
authors.initials: DC
authors.lastname: Voon
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Mauduit
authors.affiliation: Emerging Infectious Diseases Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bist
authors.affiliation: Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Bi
authors.affiliation: Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
authors.forename: Natasha Ann
authors.initials: NA
authors.lastname: Pereira
authors.affiliation: Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Emerging Infectious Diseases Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Bindu
authors.initials: B
authors.lastname: Sukumaran
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
authors.affiliation: Cancer Biology Program, Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: 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: lam_kong_peng@bti.a-star.edu.sg.
authors.forename: Kong-Peng
authors.initials: KP
authors.lastname: Lam
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056004:Molecular Dynamics Simulation; D018512:Parasitemia / Q000401:mortality / Q000473:pathology / Q000662:veterinary; D010748:Phosphopeptides / Q000032:analysis; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D000099197:STING Protein
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D053487:DEAD-box RNA Helicases; D004247:DNA; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D010748:Phosphopeptides; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C567960:DDX41 protein, mouse