Convergent evolution of viral nucleases targeting cyclic dinucleotides
- 1Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- 2Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
Abstract
Poxviruses, African swine fever virus (ASFV), and bacteriophages have independently evolved nucleases that degrade cyclic dinucleotides (CDNs), which are critical second messengers that mediate antiviral responses. This Pearl synthesizes recent advancements in our understanding of viral CDN-degrading nucleases and emphasizes three key themes. First, there is the conservation of CDN signaling mechanisms across different biological domains. Second, we observe the diverse structural adaptations of viral nucleases for CDN degradation. Finally, structural protein folds are conserved, allowing for functional replacements across species. Additionally, we discuss the therapeutic potential of targeting these nucleases with resistant CDN analogues and through structure-guided drug discovery. This convergence in viral immune evasion strategies provides valuable insights into the development of broad-spectrum antiviral therapies and offers new opportunities for enhancing immune responses in therapeutic contexts. Author summary: Cells have built-in alarm systems to detect viruses. When a virus invades, infected cells produce small signaling molecules called cyclic dinucleotides, or CDNs. These molecules alert nearby cells and trigger immune defenses. Over millions of years, viruses have found ways to disarm this alarm. Large DNA viruses such as poxviruses and African swine fever virus carry enzymes that destroy these danger signals, allowing them to evade the immune system. Bacteria use a similar alarm system to defend against their own viral invaders, phages. Phages have evolved enzymes that destroy bacterial alarm signals. Viruses that infect animals and viruses that infect bacteria have independently arrived at the same solution to the same problem. In this Pearl, we review these recently discovered viral enzymes and show how they share the same basic protein structure despite separate evolutionary paths. We also discuss how understanding these enzymes could aid the development of new antiviral drugs. One strategy is to design molecules that block the viral enzymes and restore immune defenses. Another is to create CDN-like compounds that resist degradation by these enzymes. The convergence of viral immune evasion strategies across different branches of life reveals fundamental principles of host-pathogen conflict and opens new possibilities for therapeutic intervention.
Related
- Structure and evolution-guided design of minimal RNA-guided nucleases
- Structural basis for inhibition of the lipid flippase MurJ by phage lysis protein SglPP7 suggests convergent evolution with other Sgl peptides
- Anti-CRISPR prediction using deep learning reveals an inhibitor of Cas13b nucleases
- Evolution and metabolite signaling of fumarases (class I and II): origin, function, and subcellular targeting
- Multi-Omic Integration of the miRNome and Transcriptome in Dermal Fibroblasts from Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Identifies Convergent Candidate miRNA-mRNA Regulatory Networks Linking Extracellular Matrix Remodeling and Inflammation
BibTeX
@article{li2026convergent,
title = {{Convergent evolution of viral nucleases targeting cyclic dinucleotides}},
author = {Zichen Li and Leiliang Zhang},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014605},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014605},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Convergent evolution of viral nucleases targeting cyclic dinucleotides
AU - Zichen Li
AU - Leiliang Zhang
PY - 2026
DA - 2026/09/15
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014605
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014605
AB - Poxviruses, African swine fever virus (ASFV), and bacteriophages have independently evolved nucleases that degrade cyclic dinucleotides (CDNs), which are critical second messengers that mediate antiviral responses. This Pearl synthesizes recent advancements in our understanding of viral CDN-degrading nucleases and emphasizes three key themes. First, there is the conservation of CDN signaling mechanisms across different biological domains. Second, we observe the diverse structural adaptations of viral nucleases for CDN degradation. Finally, structural protein folds are conserved, allowing for functional replacements across species. Additionally, we discuss the therapeutic potential of targeting these nucleases with resistant CDN analogues and through structure-guided drug discovery. This convergence in viral immune evasion strategies provides valuable insights into the development of broad-spectrum antiviral therapies and offers new opportunities for enhancing immune responses in therapeutic contexts. Author summary: Cells have built-in alarm systems to detect viruses. When a virus invades, infected cells produce small signaling molecules called cyclic dinucleotides, or CDNs. These molecules alert nearby cells and trigger immune defenses. Over millions of years, viruses have found ways to disarm this alarm. Large DNA viruses such as poxviruses and African swine fever virus carry enzymes that destroy these danger signals, allowing them to evade the immune system. Bacteria use a similar alarm system to defend against their own viral invaders, phages. Phages have evolved enzymes that destroy bacterial alarm signals. Viruses that infect animals and viruses that infect bacteria have independently arrived at the same solution to the same problem. In this Pearl, we review these recently discovered viral enzymes and show how they share the same basic protein structure despite separate evolutionary paths. We also discuss how understanding these enzymes could aid the development of new antiviral drugs. One strategy is to design molecules that block the viral enzymes and restore immune defenses. Another is to create CDN-like compounds that resist degradation by these enzymes. The convergence of viral immune evasion strategies across different branches of life reveals fundamental principles of host-pathogen conflict and opens new possibilities for therapeutic intervention.
SN - 1553-7374
ER -