Pyroptosis is a fulminant form of macrophage cell death, contributing to release of pro‐inflammatory cytokines. In humans, it depends on caspase 1/4‐activation of gasdermin D and is characterized by the release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1‐F2) of contemporary H5N1 and H3N2 influenza A viruses (IAV) curtails fulminant cell death of infected human macrophages. Infection of macrophages with a PB1‐F2‐deficient mutant of a contemporary IAV resulted in higher levels of caspase‐1 activation, cleavage of gasdermin D, and release of LDH and IL‐1β. Mechanistically, PB1‐F2 limits transition of NLRP3 from its auto‐repressed and closed confirmation into its active state. Consequently, interaction of a recently identified licensing kinase NEK7 with NLRP3 is diminished, which is required to initiate inflammasome assembly.

中文翻译：

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甲型流感病毒限制了人类巨噬细胞中 NLRP3-NEK7 复合物的形成和细胞焦亡

焦亡是巨噬细胞死亡的一种暴发形式，有助于释放促炎细胞因子。在人类中，它依赖于 gasdermin D 的半胱天冬酶 1/4-激活，其特点是释放细胞质内容物。病原体应用策略来避免或对抗这种宿主反应。我们在此证明，当代 H5N1 和 H3N2 甲型流感病毒 (IAV) 的一种小辅助蛋白 (PB1-F2) 可减少受感染的人类巨噬细胞的暴发性细胞死亡。用当代 IAV 的 PB1-F2 缺陷突变体感染巨噬细胞导致更高水平的 caspase-1 激活、gasdermin D 裂解以及 LDH 和 IL-1β 的释放。从机制上讲，PB1-F2 限制了 NLRP3 从其自动抑制和关闭确认到其活动状态的转变。最后，