The nucleotide-binding domain,leucine-rich-repeat containing family,pyrin domain-containing 3(NLRP3)inflammasome is essential in inflammation and inflammatory disorders.Phosphorylation at various sites on NLRP3 differ...The nucleotide-binding domain,leucine-rich-repeat containing family,pyrin domain-containing 3(NLRP3)inflammasome is essential in inflammation and inflammatory disorders.Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation.The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios,but the importance and regulation of this site has not been clarified.The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages.We also showed that Ser725 was directly phosphorylated by misshapen(Msn)/NIK-related kinase 1(MINK1),depending on the direct interaction between MINK1 and the NLRP3 LRR domain.MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis.Reactive oxygen species(ROS)upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation.Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner.Altogether,our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasomerelated diseases.展开更多
In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in thi...In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in this case,indicating the potential of application of B cell-targeting CAR-T cell therapy in severe autoimmune diseases.展开更多
Calcium is an important cell signaling intermediate known to play a critical role in T-cell receptor(TCR)-mediated activation of both developing thymocytes and mature peripheral T cells.Upon antigen engagement,the TCR...Calcium is an important cell signaling intermediate known to play a critical role in T-cell receptor(TCR)-mediated activation of both developing thymocytes and mature peripheral T cells.Upon antigen engagement,the TCR recruits PLCγ1 to the proximal signaling complex to be phosphorylated and activated by the membrane-bound kinase Itk.Activated PLCγ1 mediates the cleavage of the cell membrane lipid component PIP2 into the lipids diacylglycerol(DAG)and inositol 1,4,5-triphosphate(IP3).展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(31930038,31770954,and 31530019 to L.L.).
文摘The nucleotide-binding domain,leucine-rich-repeat containing family,pyrin domain-containing 3(NLRP3)inflammasome is essential in inflammation and inflammatory disorders.Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation.The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios,but the importance and regulation of this site has not been clarified.The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages.We also showed that Ser725 was directly phosphorylated by misshapen(Msn)/NIK-related kinase 1(MINK1),depending on the direct interaction between MINK1 and the NLRP3 LRR domain.MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis.Reactive oxygen species(ROS)upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation.Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner.Altogether,our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasomerelated diseases.
基金Our work was supported by grants from the National Natural Science Foundation of China(31930038,31770954,and 31530019 to LL).
文摘In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in this case,indicating the potential of application of B cell-targeting CAR-T cell therapy in severe autoimmune diseases.
文摘Calcium is an important cell signaling intermediate known to play a critical role in T-cell receptor(TCR)-mediated activation of both developing thymocytes and mature peripheral T cells.Upon antigen engagement,the TCR recruits PLCγ1 to the proximal signaling complex to be phosphorylated and activated by the membrane-bound kinase Itk.Activated PLCγ1 mediates the cleavage of the cell membrane lipid component PIP2 into the lipids diacylglycerol(DAG)and inositol 1,4,5-triphosphate(IP3).
