On September 21st, Molecular Cell published the latest research results of the "NLRP3 phosphorylation is an essential priming event for inflammasome activation" by the researcher Li Tao and the researcher Zhou Tao of the National Center for Biomedical Analysis. This paper reports that phosphorylation is a key molecular event in the pre-activation phase of NLRP3 inflammatory bodies (Priming), elucidating the important regulatory role of phosphorylation modification in the activation of NLRP3 inflammatory body pathways, enriching the understanding of the innate immune response mechanism . Researcher Li Tao and researcher Zhou Tao of the National Center for Biomedical Analysis are the authors of this article, and Dr. Song Nan is the first author. This study used point mutation mice prepared by Saiye Bio CRISPR/Cas9 technology .
Interpretation of the thesis:
The innate immune system is the first line of defense against pathogen invasion. The rapid detection of host by pathogens relies primarily on pattern recognition receptors. NLRP3 is an important member of the NLR pattern recognition receptor family and recognizes molecular patterns associated with pathogen and tissue damage. After activation of NLRP3, protein molecules such as apoptosis-associated spot-like protein (ASC) and caspase-1 are assembled to form a multimeric complex, an inflammatory body, which promotes inflammatory properties such as interleukin-1. The secretion of factors and the occurrence of cell charring cause a severe inflammatory response. Abnormal activation of NLRP3 inflammatory corpuscles is closely related to many major diseases such as tumors and autoimmune diseases. Therefore, in-depth study of the activation process of NLRP3 inflammatory bodies and elucidation of the regulatory mechanisms of key molecules in inflammatory body complexes is an important way to discover new targets for the treatment of these diseases.
Studies have shown that NLRP3 inflammatory body activation is regulated by two levels of signals, the first level signal is pre-activated (Priming), and the second-level signal is assembly (Assembly). At present, there are many reports on the regulation mechanism of the second-level signal, but how the first-level signal regulates the activation of inflammatory bodies remains unclear .
In this study, the researchers first identified the phosphorylation of serine (Ser194) at position 194 of the NLRP3 protein by mass spectrometry, and further found that phosphorylation at this site specifically occurs in the first-order signal of inflammatory body activation (Priming) )stage. Knock-in mice were constructed by in vitro reconstruction, phosphorylation site mutants inflammasome and bioinformatics analysis of a series of in vitro experiments in vivo methods, researchers have studied reveal NLRP3 Ser194 is phosphorylated JNK1 kinase mediated phosphorylation of the NLRP3 is deubiquitinated and oligomerized to promote NLRP3 inflammatory body activation (below) .
At the same time, the study also found that blocking the phosphorylation of this site can inhibit the self-activation of disease-associated NLRP3 mutants, providing a potential target for the treatment of NLRP3-mediated autoimmune syndrome and other diseases .
Source: BioArt - Reprinted by Saiye Biotechnology Co., Ltd.
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