title: The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response.
abstract: The induction of type I interferons by the bacterial secondary messengers cyclic di-GMP (c-di-GMP) or cyclic di-AMP (c-di-AMP) is dependent on a signaling axis that involves the adaptor STING, the kinase TBK1 and the transcription factor IRF3. Here we identified the heliase DDX41 as a pattern-recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP. Knockdown of DDX41 via short hairpin RNA in mouse or human cells inhibited the induction of genes encoding molecules involved in the innate immune response and resulted in defective activation of STING, TBK1 and IRF3 in response to c-di-GMP or c-di-AMP. Our results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by DDX41, which forms a complex with STING to signal to TBK1-IRF3 and activate the interferon response.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Kislay
authors.initials: K
authors.lastname: Parvatiyar
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Rosane M
authors.initials: RM
authors.lastname: Teles
authors.forename: Songying
authors.initials: S
authors.lastname: Ouyang
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Shankar S
authors.initials: SS
authors.lastname: Iyer
authors.forename: Shivam A
authors.initials: SA
authors.lastname: Zaver
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.forename: Shang
authors.initials: S
authors.lastname: Zeng
authors.forename: Wenwan
authors.initials: W
authors.lastname: Zhong
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.forename: Yong-jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D006152:Cyclic GMP; D053487:DEAD-box RNA Helicases; D015226:Dinucleoside Phosphates; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C528998:cyclic diadenosine phosphate; C062025:bis(3',5')-cyclic diguanylic acid; C403191:TBK1 protein, human; C501226:DDX41 protein, human