CIBIO/InBio-Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto, Vairão, Portugal.
Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal.
Front Immunol. 2021 Sep 1;12:747737. doi: 10.3389/fimmu.2021.747737. eCollection 2021.
Programmed cell death is a vital process in the life cycle of organisms. Necroptosis, an evolutionary form of programmed necrosis, contributes to the innate immune response by killing pathogen-infected cells. This virus-host interaction pathway is organized around two components: the receptor-interacting protein kinase 3 (RIPK3), which recruits and phosphorylates the mixed lineage kinase-like protein (MLKL), inducing cellular plasma membrane rupture and cell death. Critically, the presence of necroptotic inhibitors in viral genomes validates necroptosis as an important host defense mechanism. Here, we show, counterintuitively, that in different mammalian lineages, central components of necroptosis, such as RIPK3 and MLKL, are deleted or display inactivating mutations. Frameshifts or premature stop codons are observed in all the studied species of cetaceans and leporids. In carnivores' genomes, the MLKL gene is deleted, while in a small number of species from afrotheria and rodentia premature stop codons are observed in RIPK3 and/or MLKL. Interestingly, we also found a strong correlation between the disruption of necroptosis in leporids and cetaceans and the absence of the N-terminal domain of E3-like homologs (responsible for necroptosis inhibition) in their naturally infecting poxviruses. Overall, our study provides the first comprehensive picture of the molecular evolution of necroptosis in mammals. The loss of necroptosis multiple times during mammalian evolution highlights the importance of gene/pathway loss for species adaptation and suggests that necroptosis is not required for normal mammalian development. Moreover, this study highlights a co-evolutionary relationship between poxviruses and their hosts, emphasizing the role of host adaptation in shaping virus evolution.
程序性细胞死亡是生物生命周期中的一个重要过程。细胞坏死是程序性细胞坏死的一种进化形式，通过杀死被病原体感染的细胞来参与先天免疫反应。这种病毒-宿主相互作用途径围绕着两个组成部分组织起来：受体相互作用蛋白激酶 3（RIPK3），它招募并磷酸化混合谱系激酶样蛋白（MLKL），诱导细胞质膜破裂和细胞死亡。至关重要的是，病毒基因组中存在坏死抑制剂验证了坏死作为一种重要的宿主防御机制。在这里，我们出人意料地表明，在不同的哺乳动物谱系中，坏死的核心成分，如 RIPK3 和 MLKL，缺失或显示失活突变。在所有研究的鲸目动物和兔形目动物物种中都观察到移码或过早终止密码子。在食肉动物的基因组中，MLKL 基因缺失，而在少数来自非洲兽类和啮齿动物的物种中，RIPK3 和/或 MLKL 中观察到过早终止密码子。有趣的是，我们还发现兔形目动物和鲸目动物中坏死的破坏与它们自然感染的痘病毒中 E3 样同源物（负责坏死抑制）的 N 端结构域缺失之间存在很强的相关性。总的来说，我们的研究提供了哺乳动物中坏死分子进化的第一个全面图景。在哺乳动物进化过程中多次失去坏死，突出了基因/途径丢失对物种适应的重要性，并表明坏死对于正常哺乳动物的发育并非必需。此外，这项研究强调了痘病毒与其宿主之间的共同进化关系，强调了宿主适应在塑造病毒进化中的作用。
