Allantopyrone A is a fungal metabolite that uniquely possesses two α,β-unsaturated carbonyl moieties. We recently reported that allantopyrone A inhibited the nuclear factor-κB (NF-κB) signaling pathway induced by tumor necrosis factor (TNF)-α in human lung carcinoma A549 cells. In the present study, the mechanism by which allantopyrone A inhibits the TNF-α-induced signaling pathway was investigated in more detail. Allantopyrone A blocked extensive modifications to receptor-interacting protein 1 (RIP1) in the TNF receptor 1 (TNF-R1) complex. Allantopyrone A augmented the high-MW bands of TNF-R1, TNF receptor-associated factor 2, RIP1, the NF-κB subunit RelA and inhibitor of NF-κB kinase β in A549 cells, suggesting that it binds to and promotes the crosslinking of these proteins. The extracellular cysteine-rich domains of TNF-R1 were crosslinked by allantopyrone A more preferentially than its intracellular portion. The present results demonstrate that allantopyrone A interferes with multiple components of the TNF-R1 complex and blocks RIP1 modifications in the TNF-α-induced NF-κB signaling pathway.

中文翻译：

---

Allantopyrone A 干扰 TNF 受体 1 复合物的多种成分并阻断 TNF-α 诱导的信号通路中的 RIP1 修饰。

尿囊酮 A 是一种真菌代谢物，它独特地具有两个 α,β-不饱和羰基部分。我们最近报道了尿囊酮 A 抑制了人肺癌 A549 细胞中由肿瘤坏死因子 (TNF)-α 诱导的核因子-κB (NF-κB) 信号通路。在本研究中，尿囊吡喃酮 A 抑制 TNF-α 诱导的信号通路的机制得到了更详细的研究。尿囊酮 A 阻断了对 TNF 受体 1 (TNF-R1) 复合物中受体相互作用蛋白 1 (RIP1) 的广泛修饰。尿囊酮 A 增强了 A549 细胞中 TNF-R1、TNF 受体相关因子 2、RIP1、NF-κB 亚基 RelA 和 NF-κB 激酶 β 抑制剂的高分子量带，表明它结合并促进了这些蛋白质。与细胞内部分相比，尿囊吡喃酮 A 更优先地与 TNF-R1 的细胞外富含半胱氨酸的结构域交联。目前的结果表明，尿囊酮 A 干扰 TNF-R1 复合物的多种成分并阻断 TNF-α 诱导的 NF-κB 信号通路中的 RIP1 修饰。