| First Author | Pachano T | Year | 2026 |
| Journal | Cell | Volume | 189 |
| Issue | 17 | Pages | 5429-5448.e14 |
| PubMed ID | 42379168 | Mgi Jnum | J:390341 |
| Mgi Id | MGI:8376307 | Doi | 10.1016/j.cell.2026.06.017 |
| Citation | Pachano T, et al. (2026) Systematic discovery of pathogen effector functions across human pathogens and pathways. Cell |
| abstractText | Pathogens deploy effector proteins to exploit host cell biology, and most effector open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the effector ORFeome (eORFeome), a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across nuclear factor kappaB (NF-kappaB), apoptosis, p53, cGAS-STING, and major histocompatibility complex class I (MHC class I) pathways revealed novel pathway-modulating functions for hundreds of uncharacterized eORFs, unexpected activities of known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of this approach, we identified HHV6A U14 as a p53 antagonist, HHV7 U21 as a dual-function STING antagonist and MHC-I antigen display inhibitor, and adenoviral 13.6K/i-leader protein as a de novo-evolved TAP inhibitor that suppresses MHC-I display. These results establish a general framework for systematic effector annotation, uncover new mechanisms of host-pathogen interaction across kingdoms, and highlight pathogen effectors as a versatile toolkit for rewiring and probing human cellular pathways. |
