美国麻省理工学院教授Michael T. Laub其团队报道了通过一种阻止翻译的mRNA ADP-核糖基转移酶的抗病毒防御。这一研究成果发表在2024年10月23日出版的国际学术期刊《自然》上。

研究小组描述了广泛分布的抗噬菌体防御系统CmdTAC，它提供了对噬菌体的T-even家族感染的有效防御。他们的结果支持一种模型，即CmdC通过感知病毒衣壳蛋白来检测感染，最终导致毒性ADP-核糖基转移酶效应蛋白（CmdT）的激活。

该课题组发现新合成的衣壳蛋白触发伴侣CmdC与CmdTAC复合物的解离，导致抗毒素CmdA的不稳定和降解，随后释放CmdT ADP-核糖基转移酶。值得注意的是，CmdT不靶向蛋白质、DNA或结构化RNA，其他ADP-核糖基转移酶的已知靶标。

相反，CmdT修饰单链RNA内GA二核苷酸中腺嘌呤的N6位置，导致mRNA翻译被阻止并抑制病毒复制。他们的工作揭示了一种新的抗病毒防御机制和一种以前未知但广泛分布的靶向mRNA的ADP-核糖基转移酶。

据悉，宿主-病原体冲突是分子创新的关键。对病原体的免疫选择推动了整个生物学中复杂免疫机制的进化，包括细菌对噬菌体的防御。

附：英文原文

Title: Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation

Author: Vassallo, Christopher N., Doering, Christopher R., Laub, Michael T.

Issue&Volume: 2024-10-23

Abstract: Host–pathogen conflicts are crucibles of molecular innovation1,2. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacterial defence against bacteriophages3. Here we characterize the widely distributed anti-phage defence system CmdTAC, which provides robust defence against infection by the T-even family of phages4. Our results support a model in which CmdC detects infection by sensing viral capsid proteins, ultimately leading to the activation of a toxic ADP-ribosyltransferase effector protein, CmdT. We show that newly synthesized capsid protein triggers dissociation of the chaperone CmdC from the CmdTAC complex, leading to destabilization and degradation of the antitoxin CmdA, with consequent liberation of the CmdT ADP-ribosyltransferase. Notably, CmdT does not target a protein, DNA or structured RNA, the known targets of other ADP-ribosyltransferases. Instead, CmdT modifies the N6 position of adenine in GA dinucleotides within single-stranded RNAs, leading to arrest of mRNA translation and inhibition of viral replication. Our work reveals a novel mechanism of anti-viral defence and a previously unknown but broadly distributed class of ADP-ribosyltransferases that target mRNA.

DOI: 10.1038/s41586-024-08102-8

Source: https://www.nature.com/articles/s41586-024-08102-8