Regulatory sequence-based discovery of anti-defense genes in archaeal viruses

Yuvaraj Bhoobalan-Chitty (), Shuanshuan Xu, Laura Martinez-Alvarez, Svetlana Karamycheva, Kira S. Makarova, Eugene V. Koonin and Xu Peng ()
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Yuvaraj Bhoobalan-Chitty: University of Copenhagen
Shuanshuan Xu: University of Copenhagen
Laura Martinez-Alvarez: University of Copenhagen
Svetlana Karamycheva: National Library of Medicine, NIH
Kira S. Makarova: National Library of Medicine, NIH
Eugene V. Koonin: National Library of Medicine, NIH
Xu Peng: University of Copenhagen

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract In silico identification of viral anti-CRISPR proteins (Acrs) has relied largely on the guilt-by-association method using known Acrs or anti-CRISPR associated proteins (Acas) as the bait. However, the low number and limited spread of the characterized archaeal Acrs and Aca hinders our ability to identify Acrs using guilt-by-association. Here, based on the observation that the few characterized archaeal Acrs and Aca are transcribed immediately post viral infection, we hypothesize that these genes, and many other unidentified anti-defense genes (ADG), are under the control of conserved regulatory sequences including a strong promoter, which can be used to predict anti-defense genes in archaeal viruses. Using this consensus sequence based method, we identify 354 potential ADGs in 57 archaeal viruses and 6 metagenome-assembled genomes. Experimental validation identified a CRISPR subtype I-A inhibitor and the first virally encoded inhibitor of an archaeal toxin-antitoxin based immune system. We also identify regulatory proteins potentially akin to Acas that can facilitate further identification of ADGs combined with the guilt-by-association approach. These results demonstrate the potential of regulatory sequence analysis for extensive identification of ADGs in viruses of archaea and bacteria.

Date: 2024
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DOI: 10.1038/s41467-024-48074-x

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