Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Curr Opin Immunol. 2023 Aug;83:102348. doi: 10.1016/j.coi.2023.102348. Epub 2023 May 31.
The innate immune response provides the first line of defense against infection and disease. Regulated cell death (RCD) is a key component of innate immune activation, and RCD must be tightly controlled to clear pathogens while preventing excess inflammation. Recent studies have highlighted a central role for the innate immune sensor Z-DNA-binding protein 1 (ZBP1) as an activator of a form of inflammatory RCD called PANoptosis, which is regulated by a multifaceted cell death complex called the PANoptosome. In response to influenza A virus infection, ZBP1 activates the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, which then acts as an integral component of the ZBP1-PANoptosome to drive inflammatory cell death, PANoptosis. In this context, the NLRP3 inflammasome is critical for caspase-1 activation and proinflammatory cytokine interleukin (IL)-1β and IL-18 maturation, but dispensable for cell death due to functional redundancies between PANoptosome molecules. Similarly, ZBP1 is also central to the absent in melanoma 2 (AIM2)-PANoptosome; this PANoptosome forms in response to Francisella novicida and herpes simplex virus 1 infection and incorporates the AIM2 inflammasome as an integral component. In this review, we will discuss the critical roles of ZBP1 in mediating innate immune responses through inflammasomes, PANoptosomes, and PANoptosis during infection. An improved understanding of the molecular mechanisms of innate immunity and cell death will be essential for the development of targeted modalities that can improve patient outcomes by mitigating severe disease.
天然免疫反应提供了抵御感染和疾病的第一道防线。受调控的细胞死亡（RCD）是先天免疫激活的关键组成部分，必须严格控制 RCD 以清除病原体，同时防止过度炎症。最近的研究强调了天然免疫传感器 Z 型 DNA 结合蛋白 1（ZBP1）作为一种称为 PANoptosis 的炎症性 RCD 形式的激活剂的核心作用，该 RCD 受称为 PANoptosome 的多方面细胞死亡复合物调节。在流感 A 病毒感染的情况下，ZBP1 激活核苷酸结合寡聚化结构域样受体家族富含吡咯域蛋白 3（NLRP3）炎性小体，然后作为 ZBP1-PANoptosome 的一个组成部分，驱动炎症性细胞死亡，即 PANoptosis。在这种情况下，NLRP3 炎性小体对于半胱天冬酶-1 的激活和前炎性细胞因子白细胞介素（IL）-1β和 IL-18 的成熟至关重要，但由于 PANoptosome 分子之间的功能冗余，对于细胞死亡是可有可无的。同样，ZBP1 对于黑色素瘤缺失 2（AIM2）-PANoptosome 也至关重要；这种 PANoptosome 形成于弗朗西斯氏菌 novicida 和单纯疱疹病毒 1 感染时，并将 AIM2 炎性小体作为一个组成部分纳入其中。在这篇综述中，我们将讨论 ZBP1 在通过炎性小体、PANoptosomes 和 PANoptosis 在感染过程中介导先天免疫反应中的关键作用。对先天免疫和细胞死亡的分子机制的深入了解对于开发靶向治疗方法至关重要，这些方法可以通过减轻严重疾病来改善患者的预后。
