Phage anti-CRISPR control by an RNA- and DNA-binding helix–turn–helix protein

Nils Birkholz, Kotaro Kamata, Maximilian Feussner, Max E. Wilkinson, Christian Cuba Samaniego, Angela Migur, Dari Kimanius, Marijn Ceelen, Sam C. Went, Ben Usher, Tim R. Blower, Chris M. Brown, Chase L. Beisel, Zasha Weinberg, Robert D. Fagerlund, Simon A. Jackson and Peter C. Fineran ()
Additional contact information
Nils Birkholz: University of Otago
Kotaro Kamata: University of Otago
Maximilian Feussner: Leipzig University
Max E. Wilkinson: Massachusetts Institute of Technology
Christian Cuba Samaniego: Carnegie Mellon University
Angela Migur: Helmholtz Centre for Infection Research (HZI)
Dari Kimanius: CZ Imaging Institute
Marijn Ceelen: University of Otago
Sam C. Went: Durham University
Ben Usher: Durham University
Tim R. Blower: Durham University
Chris M. Brown: University of Otago
Chase L. Beisel: Helmholtz Centre for Infection Research (HZI)
Zasha Weinberg: Leipzig University
Robert D. Fagerlund: University of Otago
Simon A. Jackson: University of Otago
Peter C. Fineran: University of Otago

Nature, 2024, vol. 631, issue 8021, 670-677

Abstract: Abstract In all organisms, regulation of gene expression must be adjusted to meet cellular requirements and frequently involves helix–turn–helix (HTH) domain proteins1. For instance, in the arms race between bacteria and bacteriophages, rapid expression of phage anti-CRISPR (acr) genes upon infection enables evasion from CRISPR–Cas defence; transcription is then repressed by an HTH-domain-containing anti-CRISPR-associated (Aca) protein, probably to reduce fitness costs from excessive expression2–5. However, how a single HTH regulator adjusts anti-CRISPR production to cope with increasing phage genome copies and accumulating acr mRNA is unknown. Here we show that the HTH domain of the regulator Aca2, in addition to repressing Acr synthesis transcriptionally through DNA binding, inhibits translation of mRNAs by binding conserved RNA stem-loops and blocking ribosome access. The cryo-electron microscopy structure of the approximately 40 kDa Aca2–RNA complex demonstrates how the versatile HTH domain specifically discriminates RNA from DNA binding sites. These combined regulatory modes are widespread in the Aca2 family and facilitate CRISPR–Cas inhibition in the face of rapid phage DNA replication without toxic acr overexpression. Given the ubiquity of HTH-domain-containing proteins, it is anticipated that many more of them elicit regulatory control by dual DNA and RNA binding.

Date: 2024
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DOI: 10.1038/s41586-024-07644-1

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