EMBO J.Su Bing/Yang Xiaodong's team revealed a new mechanism for central body signaling pathways to regulate the activation of NLRP3 inflammatory small body.

Enzymeme NLRP3 inflammasome is a multi protein complex composed of receptor NLRP3, adaptor protein ASC and effector protein caspase-1. It is an important part of innate immunity.it can recognize a variety of foreign dangerous substances with different structures and functions, such as Nigerian bacteriocin, and endogenous abnormal metabolites such as cholesterol crystal, uric acid crystal and β - amyloid protein, and activate caspase-1, thus inducing cell death, maturation and secretion of pro-inflammatory cytokines interleukin-1 β (IL-1 β) and interleukin-18 (IL-18), and trigger inflammatory reaction.the abnormal activation of NLRP3 inflammasome can lead to a series of autoimmune diseases, and is closely related to diabetes, Alzheimer's disease, joint inflammation and atherosclerosis.therefore, it is very important to clarify the mechanism of NLRP3 inflammasome activation for the treatment of related inflammatory diseases.in recent years, one of the most important discoveries in the field of NLRP3 inflammasome activation regulation is that nek7, which is responsible for spindle formation and centrosome separation, can act as a switch for NLRP3 inflammasome activation and control the activation of NLRP3 inflammasome by interacting with NLRP3 protein. However, how the function of nek7 as a switch is still unclear.on November 25, 2019, the research team of Professor Su Bing and associate researcher Yang Xiaodong of Shanghai Institute of immunology, School of medicine, Shanghai Jiaotong University, published a report entitled Plk4 deubiquitation by spata2-cyld suppresses nek7 mediated NLRP3 inflammasome activation at the Centrosome's paper reveals the important function and molecular mechanism of the ubiquitination enzyme complex Spata2-CYLD regulating NEK7-NLRP3 interaction in the centrosome of cells and controlling the activation of NLRP3 inflammasome.first of all, we found that there was a strong interaction between spata2 and CYLD when we used BioID method to identify the interaction protein of CYLD.it has been reported that spata2 plays a role in TNF α - induced cell death.our study on spata2 gene knockout mice showed that spata2 deletion did not affect the growth and development of mice under normal conditions, but in the septicemia model induced by bacterial endotoxin LPS, knockout mice were more sensitive to endotoxin, showing earlier death and higher levels of serum IL-1 β and IL-18.therefore, it is speculated that spata2 can inhibit the activation of inflammatory bodies, which has been confirmed in mouse bmdm cells.further experiments showed that spata2 specifically regulates the activation of NLRP3 inflammasome, but has no effect on the activation of other inflammatory bodies.in CYLD knockout bmdm cells, NLRP3 inflammasome activation was also significantly enhanced.interference with the interaction of spata2 and CYLD also led to the disappearance of the inhibitory effect of spata2 on the activation of inflammatory bodies, indicating that spata2 and CYLD play a role in regulating inflammatory bodies in the form of complexes.interestingly, immunofluorescence assay found that spata2 was mainly located in the centrosome of cells, which was necessary for the regulation of inflammatory bodies.in the early stage of activation, a considerable proportion of NLRP3 inflammasome co localizes or connects with centrosome.the results showed that spata2 CYLD complex acted on kinase Plk4 and promoted the binding of Plk4 to nek7 by removing ubiquitination of Plk4 k63, resulting in phosphorylation of ser204 site of nek7.biochemical analysis showed that phosphorylation of this site inhibited the binding of nek7 to NLRP3, thus negatively regulating the activation of NLRP3 inflammatory bodies. this study is the first time to discover the de ubiquitinase CYLD In this study, we elucidated the molecular mechanism of signal level pathway composed of ubiquitinase and kinase to control the activation of inflammatory bodies in NLRP3 mediated by adaptor protein spata2, and revealed the important regulatory role of centrosome in the activation of inflammatory bodies, which provided potential new targets and strategies for the treatment of NLRP3 related inflammatory diseases. Professor Su Bing, Shanghai Institute of immunology, School of medicine, Shanghai Jiaotong University, is the corresponding author of this paper. Associate researcher Yang Xiaodong is the first author and co corresponding author of the paper. Technician Li Wenguo and postgraduate student Zhang Shuangyan are co second authors of the paper. original link: plate maker: Ke