title: The DHX33 RNA helicase senses cytosolic RNA and activates the NLRP3 inflammasome.
abstract: The NLRP3 inflammasome plays a major role in innate immune responses by activating caspase-1, resulting in secretion of interleukin-18 (IL-18) and IL-1β. Although cytosolic double-stranded RNA (dsRNA) and bacterial RNA are known to activate the NLRP3 inflammasome, the upstream sensor is unknown. We investigated the potential function of DExD/H-box RNA helicase family members (previously shown to sense cytosolic DNA and RNA to induce type 1 interferon responses) in RNA-induced NLRP3 inflammasome activation. Among the helicase family members tested, we found that targeting of DHX33 expression by short hairpin RNA efficiently blocked the activation of caspase-1 and secretion of IL-18 and IL-1β in human macrophages that were activated by cytosolic poly I:C, reoviral RNA, or bacterial RNA. DHX33 bound dsRNA via the helicase C domain. DHX33 interacted with NLRP3 and formed the inflammasome complex following stimulation with RNA. We therefore identified DHX33 as a cytosolic RNA sensor that activates the NLRP3 inflammasome.
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Baylor Health Care System, Dallas, TX 75204, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mitoma
authors.forename: Shino
authors.initials: S
authors.lastname: Hanabuchi
authors.forename: Taeil
authors.initials: T
authors.lastname: Kim
authors.forename: Musheng
authors.initials: M
authors.lastname: Bao
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Naoshi
authors.initials: N
authors.lastname: Sugimoto
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011070:Poly I-C / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D012313:RNA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D012329:RNA, Bacterial / Q000276:immunology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012367:RNA, Viral / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012329:RNA, Bacterial; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D012313:RNA; D020170:Caspase 1; C568925:DHX33 protein, human; D053487:DEAD-box RNA Helicases; D011070:Poly I-C