A breakthrough in understanding how viruses defeat bacterial immunity

Bacteria fend off invading viruses with molecular scissors that slice up viral DNA - a system called CRISPR that's become indispensable to gene editing. 

But viruses can fight back with a molecular trick that stops the scissors from ever being made. Writing in Nature, scientists at UC San Francisco describe how a viral "anti-CRISPR" protein sits on the bacteria's protein assembly line - which is known as a ribosome - and jams it as a CRISPR protein named Cas12 begins to form. This triggers the ribosome's quality control mechanism to destroy the emerging protein, along with its mRNA blueprint. 

The viral protein, called AcrVA2, is the only known anti-CRISPR that sabotages CRISPR this way. 

When we first put AcrVA2 into bacterial cells with Cas12, we saw Cas12 disappear. We thought anti-CRISPRs just grab Cas proteins to prevent them from cutting, but this was fundamentally different."

Joseph Bondy-Denomy, PhD, Study Senior Author and Professor, Microbiology and Immunology, University of California - San Francisco

Ribosomes make Cas12 based on genetic instructions stored in the bacteria's DNA. These instructions get copied onto a molecular blueprint called mRNA. Ribosomes then use the mRNA to assemble Cas12 - one amino acid at a time. 

The scientists, led by Nicole Marino, PhD, tested each step along the way - from DNA to mRNA to protein - to determine exactly when Cas12 went missing. AcrVA2 neither blocked the Cas12 gene, which would have prevented the Cas12 mRNA from being made, nor destroyed the mRNA in test tubes. So, the scientists looked to see if the anti-CRISPR was doing something to the ribosome. 

They found AcrVA2 lying in wait as the ribosome made protein after protein. But as soon as AcrVA2 saw the first few amino acids of Cas12 begin to emerge, it grabbed the growing protein and triggered an assembly line shutdown. 

"This anti-CRISPR has one hand for holding onto ribosomes, and another that selects just one protein: Cas12," Bondy-Denomy said. "It forces the ribosome to treat a normal message like a defective one." 

Once the ribosome was jammed, the bacteria's quality control mechanisms destroyed both the budding Cas12 protein and its mRNA blueprint. 

The discovery appears to be the first of its kind: one protein interrupting the manufacture of another on ribosomes. It's just the latest twist in our understanding of the evolutionary race between bacteria and viruses.