| dc.description.abstract | The innate immune system is considered as the first line of host defense during infection to recognize the pathogen-associated molecular patterns (PAMPs) by several classes of germline-encoded pattern-recognition receptors (PRRs) and induce the activation of NF-κB, type I interferon (IFN) and inflammasome signaling pathways, which subsequent trigger proinflammatory response to invading pathogens. Although type I interferon is required for viral clearance, aberrant production of type I interferon can have a role in immunopathology and autoimmune disorders. Thus, tight regulation of these key signaling pathways is essential for both innate and adaptive immunity to maintain the homeostasis. However, the molecular mechanisms for regulation of type I interferon are still poorly understood.
In this study we have demonstrated that the pattern-recognition receptor NLRP4 plated a negative role in regulation of type I interferon signaling and have shown detail molecular mechanisms of NLRP4-mediatde activated TBK1 degradation through K48-linked ubiquitination via the E3 ubiquitin ligase DTX4. Ectopic expression of NLRP4 inhibited type I interferon signaling induced by ligand stimulation, whereas knockdown of either NLRP4 or DTX4 abrogated TBK1 K48-linked ubiquitination and degradation and thus enhance the antiviral response. Our findings identify the NLRP4-DTX4 axis as an additional signaling cascade for TBK1 degradation to maintain immune homeostasis during antiviral innate immunity.
Autophagy plays a key role in the innate and adaptive immune system by elimination of pathogens and the induction of acquired immune response. However, the molecular mechanism of how autophagy affects the innate immunity to keep host homeostasis is still a mystery. We have identified Autophagy-related protein 13(Atg13) as a positive regulator in type I IFN signaling and antiviral response by interacting with RIG-I through Beclin1 during the initial stage of autophagy. We found the induction of autophagy can enhance the innate immune signaling and antiviral response. Our study will provide us a hint to deep understand how this ancient self-defense machinery functions in immunity.
In summary, this study characterized the function of NLRP4 and Atg13 in the regulation of type I IFN signaling and innate immune antiviral response, which provided potential therapeutic targets for enhancing host immunity against pathogen infection and inflammation associated disease. | en |
