Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Cell. 2023 Feb 16;186(4):864-876.e21. doi: 10.1016/j.cell.2022.12.041. Epub 2023 Feb 6.
A fundamental strategy of eukaryotic antiviral immunity involves the cGAS enzyme, which synthesizes 2',3'-cGAMP and activates the effector STING. Diverse bacteria contain cGAS-like enzymes that produce cyclic oligonucleotides and induce anti-phage activity, known as CBASS. However, this activity has only been demonstrated through heterologous expression. Whether bacteria harboring CBASS antagonize and co-evolve with phages is unknown. Here, we identified an endogenous cGAS-like enzyme in Pseudomonas aeruginosa that generates 3',3'-cGAMP during phage infection, signals to a phospholipase effector, and limits phage replication. In response, phages express an anti-CBASS protein ("Acb2") that forms a hexamer with three 3',3'-cGAMP molecules and reduces phospholipase activity. Acb2 also binds to molecules produced by other bacterial cGAS-like enzymes (3',3'-cUU/UA/UG/AA) and mammalian cGAS (2',3'-cGAMP), suggesting broad inhibition of cGAS-based immunity. Upon Acb2 deletion, CBASS blocks lytic phage replication and lysogenic induction, but rare phages evade CBASS through major capsid gene mutations. Altogether, we demonstrate endogenous CBASS anti-phage function and strategies of CBASS inhibition and evasion.
真核抗病毒免疫的一个基本策略涉及到 cGAS 酶，它合成 2',3'-cGAMP 并激活效应蛋白 STING。不同的细菌含有类似 cGAS 的酶，这些酶可以产生环状寡核苷酸并诱导抗噬菌体活性，称为 CBASS。然而，这种活性仅通过异源表达得到证明。是否含有 CBASS 的细菌会与噬菌体拮抗和共同进化尚不清楚。在这里，我们在铜绿假单胞菌中鉴定出一种内源性 cGAS 样酶，该酶在噬菌体感染过程中产生 3',3'-cGAMP，信号传递到磷脂酶效应物，并限制噬菌体复制。作为回应，噬菌体表达一种抗 CBASS 蛋白（"Acb2"），该蛋白与三个 3',3'-cGAMP 分子形成六聚体，并降低磷脂酶活性。Acb2 还与其他细菌 cGAS 样酶（3',3'-cUU/UA/UG/AA）和哺乳动物 cGAS（2',3'-cGAMP）产生的分子结合，表明广泛抑制基于 cGAS 的免疫。在 Acb2 缺失后，CBASS 阻断裂解噬菌体的复制和溶原诱导，但少数噬菌体通过主要衣壳基因突变逃避 CBASS。总的来说，我们证明了内源性 CBASS 抗噬菌体功能以及 CBASS 抑制和逃避的策略。
