期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2113872119
关键词
ZBP1; RIPK1; endotoxic shock; inflammation
资金
- NIH [R01 AI167245, R01 AI056234]
ZBP1 is known for its role in cell death, but it also promotes inflammatory responses to bacterial lipopolysaccharide or double-stranded RNA. ZBP1 facilitates the delivery and ubiquitination of RIPK1, sustaining the activation of inflammatory signaling cascades. This finding highlights the crucial role of ZBP1 in regulating both bacterial and viral responses.
ZBP1 is widely recognized as a mediator of cell death for its role in initiating necroptotic, apoptotic, and pyroptotic cell death pathways in response to diverse pathogenic infection. Herein, we characterize an unanticipated role for ZBP1 in promoting inflammatory responses to bacterial lipopolysaccharide (LPS) or double-stranded RNA (dsRNA). In response to both stimuli, ZBP1 promotes the timely delivery of RIPK1 to the Toll-like receptor (TLR)3/4 adaptor TRIF and M1-ubiquitination of RIPK1, which sustains activation of inflammatory signaling cascades downstream of RIPK1. Strikingly, ZBP1-mediated regulation of these pathways is important in vivo, as Zbp12/2 mice exhibited resistance to LPS-induced septic shock, revealed by prolonged survival and delayed onset of hypothermia due to decreased inflammatory responses and subsequent cell death. Further findings revealed that ZBP1 promotes sustained inflammatory responses by mediating the kinetics of proinflammatory TRIFosome complex formation, thus having a profound impact downstream of TLR activation. Given the well-characterized role of ZBP1 as a viral sensor, our results exemplify previously unappreciated crosstalk between the pathways that regulate host responses to bacteria and viruses, with ZBP1 acting as a crucial bridge between the two.
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