PDF(Pubmed)
Abstract：
The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.
摘要：
炎性小体激活的时空调控仍不清楚。为了检查炎症反应的组装和调节的潜在机制，在这里,我们对含有CARD(ASC)的凋亡相关斑点样蛋白进行免疫沉淀-质谱分析,并将NCF4/1/2鉴定为ASC结合蛋白.NCF4表达降低与结直肠癌发展和结直肠癌患者五年生存率降低相关。NCF4与NCF1和NCF2协同促进NLRP3和AIM2炎性体活化。机械上,NCF4磷酸化和puncta分布从NADPH复合物切换到核周区域，介导ASC低聚，斑点形成和炎症小体激活。NCF4用作ROS水平的传感器，在ROS产生和炎症小体激活之间建立平衡。NCF4缺乏导致小鼠严重的结直肠癌，增加转运扩增和癌前细胞，减少CD8+T和NK细胞的频率和激活，并在结直肠肿瘤发生的早期损害炎性小体-IL-18-IFN-γ轴。我们的研究暗示NCF4在确定炎性体组装的空间定位并有助于炎性体介导的抗肿瘤反应中。
