See also the associated paper by Marcelo Torres, Fangping Wan & Cesar de la Fuente-Nunez

@delafuentelab.bsky.social

www.nature.com/articles/s41...

Thank you for reading and thanks to all co-authors!

Therefore, in complex systems, proteins can serve multiple roles. Our findings highlight the importance of studying viral functions in their full biological context, and not just in overexpression setups. (10/n)

We also analyzed 24 other viral AcrIII-1 homologs in archaea. Most are not expressed early and lack strong promoters, making them unlikely to act as Acrs in vivo. (9/n)

Our data show cA4 influences viral fitness even without CRISPR systems, suggesting non-defense roles for this molecule that deserve further attention. (8/n)

In fact, ring nuclease activity isn’t required for this advantage. SIRV2 gp37 appears multifunctional, since it also interacts with host proteins and may modulate cA4-linked pathways in ways unrelated to defense. (7/n)

So, what does gp37 actually do? It binds and inhibits a host protein methyltransferase, giving the virus a fitness advantage that’s independent of CRISPR immunity. (6/n)

We confirmed this by engineering early gp29 expression using an inducible promoter. This restored Acr activity and allowed viral replication under CRISPR pressure. (5/n)

The reason for this is timing: gp37 is expressed mid/late in infection—too late to stop CRISPR-Cas, which acts early. Early expression is crucial for anti-CRISPR function. (4/n)

We tested the native homolog, gp37 from SIRV2, in its natural host. But when gp37 is expressed from the virus genome, it shows no anti-CRISPR activity. (3/n)

AcrIII-1 is a ring nuclease that degrades cA4, a key signaling molecule in type III CRISPR-Cas immunity.
Earlier studies showed that AcrIII-1 (like SIRV1 gp29) inhibits CRISPR, but only when overexpressed from plasmids in non-native systems. (2/n)