Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Mol Cell. 2022 Dec 15;82(24):4591-4610. doi: 10.1016/j.molcel.2022.11.006. Epub 2022 Dec 1.
Second-messenger-mediated signaling by cyclic oligonucleotides (cOs) composed of distinct base, ring size, and 3'-5'/2'-5' linkage combinations constitutes the initial trigger resulting in activation of signaling pathways that have an impact on immune-mediated antiviral defense against invading viruses and phages. Bacteria and archaea have evolved CRISPR, CBASS, Pycsar, and Thoeris surveillance complexes that involve cO-mediated activation of effectors resulting in antiviral defense through either targeted nuclease activity, effector oligomerization-mediated depletion of essential cellular metabolites or disruption of host cell membrane functions. Notably, antiviral defense capitalizes on an abortive infection mechanism, whereby infected cells die prior to completion of the phage replication cycle. In turn, phages have evolved small proteins that target and degrade/sequester cOs, thereby suppressing host immunity. This review presents a structure-based mechanistic perspective of recent advances in the field of cO-mediated antiviral defense, in particular highlighting the ancient evolutionary adaptation by metazoans of bacterial cell-autonomous innate immune mechanisms.
由不同碱基、环大小和 3′-5′/2′-5′连接组合组成的环状寡核苷酸 (cO) 通过第二信使介导的信号转导，构成了最初的触发因素，导致信号通路的激活，从而对免疫介导的抗病毒防御产生影响，抵御入侵的病毒和噬菌体。细菌和古菌已经进化出 CRISPR、CBASS、Pycsar 和 Thoeris 监测复合物，涉及 cO 介导的效应子激活，通过靶向核酸酶活性、效应子寡聚化介导的必需细胞代谢物耗竭或破坏宿主细胞膜功能来实现抗病毒防御。值得注意的是，抗病毒防御利用了一种流产感染机制，即感染细胞在噬菌体复制周期完成之前死亡。反过来，噬菌体进化出了靶向和降解/隔离 cO 的小蛋白，从而抑制宿主免疫。本综述从基于结构的机制角度介绍了 cO 介导的抗病毒防御领域的最新进展，特别是强调了后生动物对细菌细胞自主先天免疫机制的古老进化适应。
