Turcotte Elizabeth A, Kim Kyungsub, Eislmayr Kevin D, Goers Lisa, Mitchell Patrick S, Lesser Cammie F, Vance Russell E
Division of Immunology & Molecular Medicine, Department of Molecular & Cell Biology, University of California, Berkeley, United States.
Department of Microbiology, Harvard Medical School, Boston, United States.
bioRxiv. 2025 Feb 2:2025.02.01.636075. doi: 10.1101/2025.02.01.636075.
The NAIP-NLRC4 inflammasome senses pathogenic bacteria by recognizing the cytosolic presence of bacterial proteins such as flagellin and type III secretion system (T3SS) subunits. In mice, the NAIP-NLRC4 inflammasome provides robust protection against bacterial pathogens that infect intestinal epithelial cells, including the gastrointestinal pathogen . By contrast, humans are highly susceptible to , despite the ability of human NAIP-NLRC4 to robustly detect T3SS proteins. Why the NAIP-NLRC4 inflammasome protects mice but not humans against infection remains unclear. We previously found that human THP-1 cells infected with lose responsiveness to NAIP-NLRC4 stimuli, while retaining sensitivity to other inflammasome agonists. Using mT3Sf, a "minimal " system, to express individual secreted effector proteins, we found that the OspF effector specifically suppresses NAIP-NLRC4-dependent cell death during infection. OspF was previously characterized as a phosphothreonine lyase that inactivates p38 and ERK MAP kinases. We found that p38 was critical for rapid priming of NAIP-NLRC4 activity, particularly in cells with low NAIP-NLRC4 expression. Overall, our results provide a mechanism by which evades inflammasome activation in humans, and describe a new mechanism for rapid priming of the NAIP-NLRC4 inflammasome.
NAIP-NLRC4炎性小体通过识别细菌蛋白（如鞭毛蛋白和III型分泌系统（T3SS）亚基）的胞质存在来感知病原菌。在小鼠中，NAIP-NLRC4炎性小体为抵抗感染肠道上皮细胞的细菌病原体（包括胃肠道病原体）提供了强大的保护作用。相比之下，尽管人类的NAIP-NLRC4能够强有力地检测T3SS蛋白，但人类对（某种细菌，原文未明确）却高度易感。NAIP-NLRC4炎性小体为何能保护小鼠而非人类抵抗（该细菌）感染仍不清楚。我们之前发现，感染（该细菌）的人类THP-1细胞对NAIP-NLRC4刺激失去反应，同时对其他炎性小体激动剂仍保持敏感。使用mT3Sf（一种“最小化”系统）来表达单个分泌的效应蛋白，我们发现OspF效应蛋白在感染期间特异性抑制NAIP-NLRC4依赖性细胞死亡。OspF之前被表征为一种磷酸苏氨酸裂解酶，可使p38和ERK丝裂原活化蛋白激酶失活。我们发现p38对于NAIP-NLRC4活性的快速启动至关重要，特别是在NAIP-NLRC4表达较低的细胞中。总体而言，我们的结果提供了一种（该细菌）在人类中逃避炎性小体激活的机制，并描述了一种NAIP-NLRC4炎性小体快速启动的新机制。
