Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
EMBO Rep. 2020 Dec 3;21(12):e50421. doi: 10.15252/embr.202050421. Epub 2020 Nov 12.
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.
细胞焦亡是巨噬细胞的一种暴发性细胞死亡形式，导致促炎细胞因子的释放。在人类中，它依赖于半胱天冬酶 1/4 激活的 Gasdermin D，并以细胞质内容物的释放为特征。病原体采用策略来避免或拮抗这种宿主反应。我们在这里证明，当代 H5N1 和 H3N2 甲型流感病毒 (IAV) 的一个小辅助蛋白 (PB1-F2) 可以抑制感染的人巨噬细胞的暴发性细胞死亡。用缺乏当代 IAV 的 PB1-F2 缺失突变体感染巨噬细胞会导致 caspase-1 激活、Gasdermin D 切割以及 LDH 和 IL-1β 的释放增加。从机制上讲，PB1-F2 限制了 NLRP3 从其自动抑制和封闭构象向其活性状态的转变。因此，与 NLRP3 相互作用的最近发现的许可激酶 NEK7 减少，这对于起始炎性小体组装是必需的。
