PDF(Pubmed)
Abstract：
Inflammasomes are filamentous signaling platforms essential for host defense against various intracellular calamities such as pathogen invasion and genotoxic stresses. However, dysregulated inflammasomes cause an array of human diseases including autoinflammatory disorders and cancer. It was recently identified that endogenous pyrin-only-proteins (POPs) regulate inflammasomes by directly inhibiting their filament assembly. Here, by combining Rosetta in silico, in vitro, and in cellulo methods, we investigate the target specificity and inhibition mechanisms of POPs. We find here that POP1 is ineffective in directly inhibiting the central inflammasome adaptor ASC. Instead, POP1 acts as a decoy and targets the assembly of upstream receptor pyrin-domain (PYD) filaments such as those of AIM2, IFI16, NLRP3, and NLRP6. Moreover, not only does POP2 directly suppress the nucleation of ASC, but it can also inhibit the elongation of receptor filaments. In addition to inhibiting the elongation of AIM2 and NLRP6 filaments, POP3 potently suppresses the nucleation of ASC. Our Rosetta analyses and biochemical experiments consistently suggest that a combination of favorable and unfavorable interactions between POPs and PYDs is necessary for effective recognition and inhibition. Together, we reveal the intrinsic target redundancy of POPs and their inhibitory mechanisms.
摘要：
炎性体是丝状信号平台，对于宿主防御各种细胞内灾难如病原体入侵和遗传毒性应激至关重要。然而,异常调节的炎性体会导致一系列人类疾病，包括自身炎症性疾病和癌症。最近发现内源性仅Pyrin蛋白（POPs）通过直接抑制其细丝组装来调节炎性体。这里,通过将罗塞塔与硅片结合，在体外，在脂肪法中，我们研究了POPs的靶特异性和抑制机制。我们在这里发现POP1在直接抑制中央炎性体适配器ASC方面无效。相反，POP1充当诱饵并靶向上游受体pyrin结构域（PYD）细丝的组装，例如AIM2，IFI16，NLRP3和NLRP6的细丝。此外，POP2不仅直接抑制ASC的成核，但它也可以抑制受体丝的伸长。除了抑制AIM2和NLRP6细丝的伸长外，POP3有效抑制ASC的成核。我们的Rosetta分析和生化实验一致表明，有效识别和抑制POPs和PYDs之间有利和不利相互作用的组合是必要的。一起,我们揭示了POPs的内在靶标冗余及其抑制机制。
