title: Poly IC triggers a cathepsin D- and IPS-1-dependent pathway to enhance cytokine production and mediate dendritic cell necroptosis.
abstract: RIG-I-like receptors (RLRs) sense virus-derived RNA or polyinosinic-polycytidylic acid (poly IC) to exert antiviral immune responses. Here, we examine the mechanisms underlying the adjuvant effects of poly IC. Poly IC was taken up by dendritic cells (DCs), and it induced lysosomal destabilization, which, in turn, activated an RLR-dependent signaling pathway. Upon poly IC stimulation, cathepsin D was released into the cytoplasm from the lysosome to interact with IPS-1, an adaptor molecule for RLRs. This interaction facilitated cathepsin D cleavage of caspase 8 and the activation of the transcription factor NF-κB, resulting in enhanced cytokine production. Further recruitment of the kinase RIP-1 to this complex initiated the necroptosis of a small number of DCs. HMGB1 released by dying cells enhanced IFN-β production in concert with poly IC. Collectively, these findings suggest that cathepsin D-triggered, IPS-1-dependent necroptosis is a mechanism that propagates the adjuvant efficacy of poly IC.
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Tsuchida
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kozaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kyung-Sue
authors.initials: KS
authors.lastname: Shin
authors.forename: Himanshu
authors.initials: H
authors.lastname: Kumar
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002402:Cathepsin D / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D020690:GTPase-Activating Proteins / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D007113:Immunity, Innate; D056747:Immunomodulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009336:Necrosis / Q000276:immunology; D011070:Poly I-C / Q000276:immunology; D011485:Protein Binding; D015398:Signal Transduction / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002402:Cathepsin D; D016207:Cytokines; D020690:GTPase-Activating Proteins; D024243:HMGB1 Protein; D011070:Poly I-C; C512612:MAVS protein, mouse; C490620:Ralbp1 protein, mouse