Poly IC Triggers a Cathepsin D- and IPS-1-Dependent Pathway to Enhance Cytokine Production and Mediate Dendritic Cell Necroptosis

• Published in: Immunity (Cambridge, Mass.) Vol. 38; no. 4; pp. 717 - 728
• Main Authors: Zou, Jian, Kawai, Taro, Tsuchida, Tetsuo, Kozaki, Tatsuya, Tanaka, Hiroki, Shin, Kyung-Sue, Kumar, Himanshu, Akira, Shizuo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.04.2013; Elsevier Limited
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Cathepsin D - metabolism; Cells, Cultured; Cytokines; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - virology; Deoxyribonucleic acid; DNA; Flow cytometry; GTPase-Activating Proteins - metabolism; HMGB1 Protein - metabolism; Immune system; Immunity, Innate; Immunomodulation; Infections; Kinases; Ligands; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mitochondria; Necrosis - immunology; Poly I-C - immunology; Protein Binding; Proteins; Signal Transduction - immunology; Studies
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2012.12.007

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. ► Poly IC is taken up by dendritic cells to activate an IPS-1-dependent pathway ► Cathepsin D is released into the cytoplasm upon poly IC stimulation to interact with IPS-1 ► Cathepsin D and IPS-1 complex promotes necroptosis ► HMGB1 is released and enhances IFN-β production in concert with poly IC