Basic Medical College, Qingdao University, Qingdao, China.
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, China.
Front Cell Infect Microbiol. 2020 Sep 30;10:511798. doi: 10.3389/fcimb.2020.511798. eCollection 2020.
Activation of the NLRP3 inflammasome requires the expression of NLRP3, which is strictly regulated by its capacity to directly recognize microbial-derived substances. Even though the involvement of caspase-1 activation in macrophages NLRP3 and NLRC4 has been discovered, the accurate mechanisms by which infection triggers NLRP3 activation remain inadequately understood. Here, we demonstrate that IpaH4.5, a T3SS effector, triggers inflammasome activation by regulating NLRP3 expression through the E3 ubiquitin ligase activity of IpaH4.5. First, we found that IpaH4.5 interacted with NLRP3. As a result, IpaH4.5 modulated NLRP3 protein stability and inflammasome activation. Bacteria lacking IpaH4.5 had dramatically reduced ability to induce pyroptosis. Our results identify a previously unrecognized target of IpaH4.5 in the regulation of inflammasome signaling and clarify the molecular basis for the cytosolic response to the T3SS effector.
NLRP3 炎性小体的激活需要 NLRP3 的表达，而 NLRP3 的表达受到其直接识别微生物来源物质的能力的严格调控。尽管已经发现 caspase-1 在巨噬细胞 NLRP3 和 NLRC4 中的激活作用，但触发 NLRP3 激活的确切机制仍未得到充分理解。在这里，我们证明 T3SS 效应蛋白 IpaH4.5 通过 IpaH4.5 的 E3 泛素连接酶活性调节 NLRP3 的表达来触发炎性小体的激活。首先，我们发现 IpaH4.5 与 NLRP3 相互作用。结果，IpaH4.5 调节 NLRP3 蛋白稳定性和炎性小体激活。缺乏 IpaH4.5 的细菌诱导细胞焦亡的能力显著降低。我们的结果确定了 IpaH4.5 在调节炎性体信号中的一个以前未被识别的靶标，并阐明了细胞质对 T3SS 效应蛋白的细胞反应的分子基础。
