Looks like the previous link is not working... here's a working link! www.biorxiv.org/content/10.1...

Also, this would not have been possible without many collaborators and their clone and ORF collections. @interactome.bsky.social @legionella.bsky.social @hayleyjnewton.bsky.social @fuxmanlab.bsky.social @samgru.bsky.social & Matt Weirauch, Leah Kottayan, Sebastian Lourido, Daniel Schramek et al.

Link to preprint: www.biorxiv.org/content/2025...

This has been an amazing collaborative project that keeps on giving. We now have a new 3x larger eORFeome and we will dive deep into pathogen and host biology. If you are interested in scalable approaches to study effectors and their interactions with the host, get in touch! 8/8

Remarkably, 13.6K is encoded on the opposite strand of the essential E2B DNA polymerase and only found in primate adenoviruses. Thus, its birth required a novel alternative splicing event and the emergence of a de novo ORF without compromising the polymerase function! 7/8

The 13.6K open reading frame is encoded in an alternatively spliced exon of the tripartite leader sequence, the constant 5' element discovered by Phil Sharp and Richard Roberts in their classic work. 6/8

We also describe how adenoviruses have evolved a new immunoevasin from scratch. We identified adenoviral i-leader/13.6K proteins as novel inhibitors of the TAP complex, which translocates cytosolic peptides to the MHC-I complex in the ER. 5/8

We discovered HHV7 U21 as a multifunctional immunoevasin. Not only does it inhibit MHC-I surface display (shown by the Ploegh lab) but it is also induces STING degradation. Thus, it suppresses both adaptive and innate immune responses with distinct domains. 4/8

The screens yielded MANY novel regulators of these pathways alongside previously known ones. A few highlights: We identified HHV6A U14 as a p53 antagonist that interacts with its DNA-binding domain in a similar manner to Large T antigen and inhibits p53 activation. 3/8

Instead of focusing on a single pathogen, we assembled the effector ORFeome (eORFeome), a collection of ~4,000 ORFs representing viral proteins and secreted effectors from bacteria and parasites. We used pooled screens to identify effectors that target central host pathways. 2/8