title: EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex.
abstract: Activation of NLRP3 inflammasome is important for effective host defense against invading pathogen. Together with apoptosis-associated speck-like protein containing CARD domain (ASC), NLRP3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (IL-1β), an important pro-inflammatory cytokine. IL-1β subsequently plays critical roles in inflammatory responses by activating immune cells and inducing many secondary pro-inflammatory cytokines. Although the role of NLRP3 inflammasome in immune response is well defined, the mechanism underlying its assembly modulated by pathogen infection remains largely unknown. Here, we identified a novel mechanism by which enterovirus 71 (EV71) facilitates the assembly of NLRP3 inflammasome. Our results show that EV71 induces production and secretion of IL-1β in macrophages and peripheral blood mononuclear cells (PBMCs) through activation of NLRP3 inflammasome. EV71 replication and protein synthesis are required for NLRP3-mediated activation of IL-1β. Interestingly, EV71 3D protein, a RNA-dependent RNA polymerase (RdRp) was found to stimulate the activation of NLRP3 inflammasome, the cleavage of pro-caspase-1, and the release of IL-1β through direct binding to NLRP3. More importantly, 3D interacts with NLRP3 to facilitate the assembly of inflammasome complex by forming a 3D-NLRP3-ASC ring-like structure, resulting in the activation of IL-1β. These findings demonstrate a new role of 3D as an important player in the activation of inflammatory response, and identify a novel mechanism underlying the modulation of inflammasome assembly and function induced by pathogen invasion.
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Wenbiao
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yecheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Fang
authors.identifier: 0000-0003-0972-9968
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Kailang
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yingle
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
mesh_terms: D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D029821:Enterovirus A, Human / Q000378:metabolism / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000276:immunology / Q000473:pathology* / Q000821:virology; D004789:Enzyme Activation / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D017361:Viral Nonstructural Proteins; D012324:RNA-Dependent RNA Polymerase; D020170:Caspase 1