Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-05, Vol.111 (20), p.7385-7390
• Main Authors: Philip, Naomi H., Dillon, Christopher P., Snyder, Annelise G., Fitzgerald, Patrick, Wynosky-Dolfi, Meghan A., Zwack, Erin E., Hu, Baofeng, Fitzgerald, Louise, Mauldin, Elizabeth A., Copenhaver, Alan M., Shin, Sunny, Wei, Lei, Parker, Matthew, Zhang, Jinghui, Oberst, Andrew, Green, Douglas R., Brodsky, Igor E.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bacteria; Bacterial Proteins - genetics; Biological Sciences; Caspase 1 - metabolism; Caspase 8 - metabolism; caspase-1; caspase-8; Cell death; Cytokines; cytotoxicity; Enzyme Activation; Fas-Associated Death Domain Protein - metabolism; Gene Expression Regulation, Enzymologic; genes; immune response; Immunity, Innate; Infections; inflammation; Liver; Macrophages; MAP Kinase Signaling System; Mice; Mice, Transgenic; mitogen-activated protein kinase; Monocytes; Necrosis; NF-kappa B - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; signal transduction; Toll-like receptors; transcription factor NF-kappa B; virulence; Yersinia; Yersinia infections; Yersinia Infections - microbiology; Yersinia pestis; Yersinia pseudotuberculosis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1403252111

Toll-like receptor signaling and subsequent activation of NF-κB– and MAPK-dependent genes during infection play an important role in antimicrobial host defense. The YopJ protein of pathogenic Yersinia species inhibits NF-κB and MAPK signaling, resulting in blockade of NF-κB–dependent cytokine production and target cell death. Nevertheless, Yersinia infection induces inflammatory responses in vivo. Moreover, increasing the extent of YopJ-dependent cytotoxicity induced by Yersinia pestis and Yersinia pseudotuberculosis paradoxically leads to decreased virulence in vivo, suggesting that cell death promotes anti- Yersinia host defense. However, the specific pathways responsible for YopJ-induced cell death and how this cell death mediates immune defense against Yersinia remain poorly defined. YopJ activity induces processing of multiple caspases, including caspase-1, independently of inflammasome components or the adaptor protein ASC. Unexpectedly, caspase-1 activation in response to the activity of YopJ required caspase-8, receptor-interacting serine/threonine kinase 1 (RIPK1), and Fas-associated death domain (FADD), but not RIPK3. Furthermore, whereas RIPK3 deficiency did not affect YopJ-induced cell death or caspase-1 activation, deficiency of both RIPK3 and caspase-8 or FADD completely abrogated Yersinia -induced cell death and caspase-1 activation. Mice lacking RIPK3 and caspase-8 in their hematopoietic compartment showed extreme susceptibility to Yersinia and were deficient in monocyte and neutrophil-derived production of proinflammatory cytokines. Our data demonstrate for the first time to our knowledge that RIPK1, FADD, and caspase-8 are required for YopJ-induced cell death and caspase-1 activation and suggest that caspase-8–mediated cell death overrides blockade of immune signaling by YopJ to promote anti- Yersinia immune defense.