BPOZ参与调控经典及非经典炎症小体激活的分子机制研究

Inflammasomes are cytosolic multi-protein complexes assembled by intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and initiate innate immune responses to invading pathogens and danger signals by activating caspase-1. Caspase-1 activation leads to maturation and release of the proinflammatory cytokines interleukin IL-1β and IL-18 as well as a lytic inflammatory cell death termed pyroptosis. Recently, a novel non-canonical inflammasome was described that activates Caspase-11, a proinflammatory caspase required for LPS-induced lethality. Caspase-1 and Caspase-11 have both distinct and overlapping roles in the release of IL-1α and IL-1β and the induction of cell death. However, the precise regulation of Caspase-1 and Caspase-11 remains largely elusive. In this study, we report that BPOZ-deficient mice were more susceptible to mortality in LPS sepsis models and were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis. Macrophages from BPOZ-deficient mice also exhibited defective IL-1β secretion, Caspase-1, and Caspase-11 activation induced by a variety of canonical and noncanonical stimulus. Mechanistically, BPOZ interacted with Caspase-1 and Caspase-11. Peptide cutter analysis showed that BPOZ contains an aspartic acid residue (D246) critical for Caspase-1 binding, which occupies the substrate site of caspase-1 to inhibit its activation. Here in this study, we would like to delineate the biological function of BPOZ in inflammasome signaling pathway and uncovering the mechanism behind in detail.

炎症小体包括Caspase-1依赖的经典以及Caspase-11依赖的非经典炎症小体。Caspase-1、-11在细胞中的活性受到精确调控，但是对Caspase-11以及二者协同调控的研究知之甚少。我们前期研究发现， BPOZ敲除小鼠对LPS诱导的败血症模型以及DSS诱导的肠炎模型更加敏感，而且BPOZ敲除小鼠血清中IL-1β的水平更高。此外，在各种经典及非经典炎症小体激活物刺激下，BPOZ敲低的人巨噬细胞上清中分泌更多的IL-1β。初步研究显示BPOZ能够同时与Caspase-1、-11发生相互作用。生物信息学软件预测结果显示，BPOZ很有可能是Caspase-1的伪底物。本项目将进一步确立BPOZ负调控炎症小体激活这个生物学现象，研究BPOZ与Caspase-1、-11的相互作用及其生理学意义，揭示BPOZ调控炎症小体信号通路的分子机制，为抗炎及抗感染药物开发提供潜在的可能靶点。