Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem, Israel.
Research Infrastructure Facility, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem, Israel.
PLoS Pathog. 2024 Jul 16;20(7):e1012320. doi: 10.1371/journal.ppat.1012320. eCollection 2024 Jul.
Apoptosis, a major form of programmed cell death, is an essential component of host defense against invading intracellular pathogens. Viruses encode inhibitors of apoptosis to evade host responses during infection, and to support their own replication and survival. Therefore, hosts and their viruses are entangled in a constant evolutionary arms race to control apoptosis. Until now, apoptosis in the context of the antiviral immune system has been almost exclusively studied in vertebrates. This limited phyletic sampling makes it impossible to determine whether a similar mechanism existed in the last common ancestor of animals. Here, we established assays to probe apoptosis in the sea anemone Nematostella vectensis, a model species of Cnidaria, a phylum that diverged approximately 600 million years ago from the rest of animals. We show that polyinosinic:polycytidylic acid (poly I:C), a synthetic long double-stranded RNA mimicking viral RNA and a primary ligand for the vertebrate RLR melanoma differentiation-associated protein 5 (MDA5), is sufficient to induce apoptosis in N. vectensis. Furthermore, at the transcriptomic level, apoptosis related genes are significantly enriched upon poly(I:C) exposure in N. vectensis as well as bilaterian invertebrates. Our phylogenetic analysis of caspase family genes in N. vectensis reveals conservation of all four caspase genes involved in apoptosis in mammals and revealed a cnidarian-specific caspase gene which was strongly upregulated. Altogether, our findings suggest that apoptosis in response to a viral challenge is a functionally conserved mechanism that can be traced back to the last common ancestor of Bilateria and Cnidaria.
细胞凋亡是一种主要的程序性细胞死亡形式，是宿主防御入侵细胞内病原体的重要组成部分。病毒编码凋亡抑制剂，以在感染过程中逃避宿主反应，并支持自身复制和存活。因此，宿主及其病毒在控制凋亡的持续进化军备竞赛中纠缠不清。到目前为止，抗病毒免疫系统中的细胞凋亡几乎仅在脊椎动物中进行了研究。这种有限的系统发育采样使得无法确定在动物的最后共同祖先中是否存在类似的机制。在这里，我们建立了在海葵 Nematostella vectensis 中探测细胞凋亡的测定方法，海葵是刺胞动物门（Cnidaria）的一个模式物种，刺胞动物门与其他动物在大约 6 亿年前分化。我们表明，多聚肌苷酸：多聚胞苷酸（poly I:C），一种模拟病毒 RNA 的合成长双链 RNA，是脊椎动物 RLR 黑色素瘤分化相关蛋白 5（MDA5）的主要配体，足以诱导 N. vectensis 细胞凋亡。此外，在转录组水平上，poly(I:C) 暴露后，N. vectensis 以及两侧对称无脊椎动物中的凋亡相关基因明显富集。我们对 N. vectensis 中的胱天蛋白酶家族基因进行的系统发育分析揭示了所有参与哺乳动物细胞凋亡的四个胱天蛋白酶基因的保守性，并揭示了一个强烈上调的刺胞动物特异性胱天蛋白酶基因。总之，我们的研究结果表明，对病毒攻击的细胞凋亡是一种功能保守的机制，可以追溯到两侧对称动物和刺胞动物的最后共同祖先。
