The Panoptes system uses decoy cyclic nucleotides to defend against phage

• 成果类型: Article
• 署名作者: Sullivan, Ashley E.; Nabhani, Ali; Izrailevsky, Daniel S.; Schinkel, Kate; Hoffman, Charlotte R. K.; Robbins, Laurel K.; Nagy, Toni A.; Duncan, Melissa L.; Ledvina, Hannah E.; Erbse, Annette H.; Kibby, Emily M.; Tak, Uday; Dinh, David M.; Ednacot, Eirene Marie Q.; Nguyen, Christy M.; Burroughs, A. Maxwell; Aravind, L.; Whiteley, Aaron T.; Morehouse, Benjamin R.
• 署名单位: University of Colorado System; University of Colorado Boulder; University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; National Institutes of Health (NIH) - USA; NIH National Library of Medicine (NLM); Division of Intramural Research (DIR); University of California System; University of California Irvine; University of California System; University of California Irvine
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09557-z
• 发表日期: 2025-11-27
• 关键词: protein-sequence; immune-system; psi-blast; bacteria; enzymes; cgas; dna

摘要

Bacteria combat phage infection using antiphage systems and many systems generate nucleotide-derived second messengers upon infection that activate effector proteins to mediate immunity1. Phages respond with counter-defences that deplete these second messengers, leading to an escalating arms race with the host. Here we outline an antiphage system we call Panoptes that indirectly detects phage infection when phage proteins antagonize the nucleotide-derived second-messenger pool. Panoptes is a two-gene operon, optSE, wherein OptS is predicted to synthesize a nucleotide-derived second messenger and OptE is predicted to bind that signal and drive effector-mediated defence. Crystal structures show that OptS is a minimal CRISPR polymerase (mCpol) domain, a version of the polymerase domain found in type III CRISPR systems (Cas10). OptS orthologues from two distinct Panoptes systems generated cyclic dinucleotide products, including 2 ',3 '-cyclic diadenosine monophosphate (2 ',3 '-c-di-AMP), which we showed were able to bind the soluble domain of the OptE transmembrane effector. Panoptes potently restricted phage replication, but phages that had loss-of-function mutations in anti-cyclic oligonucleotide-based antiphage signalling system (CBASS) protein 2 (Acb2) escaped defence. These findings were unexpected because Acb2 is a nucleotide 'sponge' that antagonizes second-messenger signalling. Our data support the idea that cyclic nucleotide sequestration by Acb2 releases OptE toxicity, thereby initiating inner membrane disruption, leading to phage defence. These data demonstrate a sophisticated immune strategy that bacteria use to guard their second-messenger pool and turn immune evasion against the virus.