8h2x
Structure of Acb2
Structural highlights
FunctionACB2_BPPP3 Antagonizes CBASS (cyclic oligonucleotide-based antiphage signaling system) (PubMed:36750095). Binds and sequesters host-produced 3',3'-cyclic GMP-AMP (cGAMP) with a dissociation constant of about 87 nM; each homohexamer binds 3 cGAMP molecules with 1 cGAMP molecule binding to 2 monomers (PubMed:36750095). Sequestration of cGAMP inhibits the cGAMP-activated phospholipase activity of host CBASS effector protein CapV (PubMed:36750095). Does not degrade the cyclic nucleotide (PubMed:36750095). Also binds other cyclic dinucleotides including; 2',3'-cyclic GMP-AMP, cyclic-di-AMP, c-di-UMP and c-UMP-AMP with high affinity, only weakly to c-UMP-GMP and not to cyclic-di-GMP (PubMed:36750095). Also antagonizes the effector protein of P.aeruginosa type I-A and type I-B CBASS systems (capV in ATCC 33351 and a membrane protein in strain JD332 respectively) (PubMed:36750095).[1] Publication Abstract from PubMedA 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. Bacteriophages inhibit and evade cGAS-like immune function in bacteria.,Huiting E, Cao X, Ren J, Athukoralage JS, Luo Z, Silas S, An N, Carion H, Zhou Y, Fraser JS, Feng Y, Bondy-Denomy J Cell. 2023 Feb 16;186(4):864-876.e21. doi: 10.1016/j.cell.2022.12.041. Epub 2023 , Feb 6. PMID:36750095[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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