Abstract
Yersinia pestis uses type III effector proteins to target eukaryotic signaling systems. The Yersinia outer protein (Yop) M effector from the Y. pestis strain is a critical virulence determinant; however, its role in Y. pestis pathogenesis is just beginning to emerge. Here we first identify YopM as the structural mimic of the bacterial IpaH E3 ligase family in vitro, and establish that the conserved CLD motif in its N-terminal is responsible for the E3 ligase function. Furthermore, we show that NLRP3 is a novel target of the YopM protein. Specially, YopM associates with NLRP3, and its CLD ligase motif mediates the activating K63-linked ubiquitylation of NLRP3; as a result, YopM modulates NLRP3-mediated cell necrosis. Mutation of YopM E3 ligase motif dramatically reduces the ability of Y. pestis to induce HMGB1 release and cell necrosis, which ultimately contributes to bacterial virulence. In conclusion, this study has identified a previously unrecognized role for YopM E3 ligase activity in the regulation of host cell necrosis and plague pathogenesis.
Highlights
Inflammatory reactions in response to pathogen infection are orchestrated by complex soluble mediators, including locally released cytokines and chemokines, such as IL-1β and IL-18.1–4 The activation of caspase-1 is essential for the processing of pro-IL-1β and pro-IL-18 and the secretion of their mature biologically active forms.[5]
Since NLRP3 interacted with YopM, we suggested that NLRP3 might be a potential substrate of YopM E3 ubiquitin ligase
NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) respond rapidly to PAMPs found within the host cell cytosol and trigger cell death.[42,43]
Summary
Inflammatory reactions in response to pathogen infection are orchestrated by complex soluble mediators, including locally released cytokines and chemokines, such as IL-1β and IL-18.1–4 The activation of caspase-1 is essential for the processing of pro-IL-1β and pro-IL-18 and the secretion of their mature biologically active forms.[5]. The best-characterized inflammasome is the NOD-like receptor (NLR)-family pyrin domain-containing 3 (NLRP3, known as Nalp[3] or cryopyrin) inflammasome, which can be activated by a wide range of stimuli.[14,15,16,17,18] Two different types of NLRP3-dependent cell death have been reported.[19]. Pyroptosis is an inflammatory program of cell death, which is caspase-1-dependent.[10] Activation of pyroptosis promotes innate immune responses, protects against numerous pathogens, and enables clearance of invading pathogens. The role of NLRP3-dependent necrosis in Y. pestis pathogenesis remains further investigation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
