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Nature research paper: Diverse bacterial pattern recognition receptors sense the core phage proteome go.nature.com/45fpXCZ

Come work on exciting AI for biology projects in Paris!! 🇫🇷 Details and application below, deadline sept 1st!

Thanks Alex!

Thanks for your efforts, Erin!

Thanks so much, Aude!

Thank you, Tera! I have quite enjoyed your work on the cell immunity side

thanks!

Thanks so much!

Ad forthcoming, but I am hiring for a postdoc or staff scientist to advance related investigations of the virus-host conflict. This position is ~80-100% computational, but with opportunities for experimental work if desired. If interested, shoot me an email with your CV! Reposts appreciated! 15/15

All of this work is thanks to my wonderful co-authors. A big thanks and congratulations to Lorenzo Profeta, who led the domain work, @erinedoherty.bsky.social who led the biochemistry, and the many other bluesky-less colleagues and collaborators who made this work possible :) 14/15

TVC is under development, and we welcome feedback! The goal is for it to serve as a unified source of viral protein information - no more "wait, what is this domain anyway?". 13/15

Finally, a note on TVC. We've released tvc.apps.aithyra.at to enable exploration by the community. Here, for most viral proteins you can see domain-level annotations at the sequence and structure level. You can also chat with an AI about the database, and do seq/struc searches against TVC 12/15

Collectively, we argue that pathogen immune antagonism uses a conserved structural language, and that deciphering this language can allow us to anticipate and identify emerging mechanisms of pathogenesis throughout the tree of life. Read the manuscript for more! 11/15

We found that dsRBDs are widespread in the viral proteome, and that diverse eukaryotic viral and phage dsRBDs can restrict dsRNA-sensing in human cells! So, the dsRBD fold is another recurrently-adapted structural feature involved in pan-viral immune antagonism. 10/15

Next, we looked at the double-stranded RNA binding domain (dsRBD) fold, which is used by some eukaryotic RNA viruses to evade human dsRNA-sensing pathways. Curiously, the phage protein Acb4, which inhibits cGAS-like enzymes by sequestering cGAMP, is also an adapted dsRBD. So, we dug in. 9/15

We found that viral DHH and HD-GYP PDEs can degrade 3'3' cGAMP, and can suppress cGAMP-mediated STING activation in human cells. This suggests that PDE folds capable of immune antagonism are widespread, and shows a fascinating connection between cGAMP regulation by bacterial and viral pathogens 8/15

Protein structure searches revealed several viral HD-GYP and a large number of viral DHH PDEs. Phylogenetic analyses revealed evidence of pervasive horizontal gene transfer of DHH PDEs, often from bacteria to bacterial viruses. DHH PDEs are also present in some mimiviruses that infect amoeba 7/15

Next, we investigated folds capable of immune antagonism. To start, we took inspiration from bacterial pathogens. M. tuberculosis encodes the DHH-family PDE CdnP to degrade human 2'3' cGAMP, while V. cholerae encodes the HD-GYP family PDEs called v-cGAPs to regulate bacterial 3'3'-cGAMP levels 6/15

With this domain-level information, we also could systematically assess how domains co-occur. Using this method, we identified a diverse and widespread family of multi-domain viral proteins reconstituting the Mre11-Rad50 multiprotein complex involved in cellular DNA repair 5/15

We separated these proteins into 790K distinct protein domains and systematically mapped their relationships and potential annotations. We found that protein structure alignments give putative annotations for 88% of well-folded domains (compared to 12% with sequence methods!) 4/15