Discovery of human gut phage-encoded anti-CRISPR proteins unveils diverse mechanisms for phages to evade type II CRISPR immunity

 Highlights

  • •
    Type II CRISPR-Cas systems are highly prevalent in the human gut
  • •
    Gut phages harbor diverse type II CRISPR inhibitors, including one for type II-B
  • •
    Members of the GutAcraca family share similar structures but have diverse sequences
  • •
    GutAcraca members inhibit bacterial immunity and regulate their own production

Summary

Phages encode diverse anti-CRISPR (Acr) proteins to counteract bacterial CRISPR-Cas systems. However, gut phage Acrs remain poorly characterized. Using an integrated bioinformatics and high-throughput functional screening approach, we identify 651 phage-encoded positive Acr candidates that target type II CRISPR systems, which predominate in the human gut. Among these, a subset of Acrs is verified through plasmid interference assays, with plaque assays confirming CRISPR-Cas inhibitory activity for 36 Acr candidates. Mechanistic characterization of five Acrs, including the Acr against subtype II-B systems (AcrIIB-1), reveals distinct inhibition strategies. Remarkably, 213 positive Acr candidates, designated here as GutAcraca, exhibit structural convergence by adopting similar folds and exhibit dual functionality: transcription regulation to support their production and inhibition of CRISPR-Cas systems. These GutAcraca are widely distributed across microbial species (detected in 26% of species). Our work uncovers the extensive diversity of phage-encoded Acrs in the human gut and highlights their potential as biotechnology tools.

Read full article at:
https://www.sciencedirect.com/science/article/abs/pii/S1931312826000855



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