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Pachano, T.* ; Leng, H.* ; Dugied, G.* ; Tribble, T.* ; Loubiere, V.* ; Lee, Y.* ; Rauh, F.* ; Manon, V.* ; Yuan, K.* ; Nurtanto, J.* ; Schleiffer, A.* ; Young, V. ; Weller, B. ; Lyons, E.A.* ; Hass, M.R.* ; Kottyan, L.C.* ; Weirauch, M.T.* ; Fuxman Bass, J.I.* ; Newton, H.J.* ; Ensminger, A.W.* ; Falter-Braun, P. ; Chen, J.* ; Schramek, D.* ; Stark, A.* ; Taipale, M.*

Systematic discovery of pathogen effector functions across human pathogens and pathways.

Cell 189, 5429-5448 (2026)
Verlagsversion Forschungsdaten DOI
Open Access Hybrid
Creative Commons Lizenzvertrag
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 κB (NF-κB), 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Effectors ; Functional Genomics ; High-throughput Screening ; Host-pathogen Interactions ; Human Signaling Pathways ; Orfeome ; P53 ; Pathogens ; Sting ; Viral Proteins; I Mhc Molecules; Large T-antigen; Gene-expression; Endoplasmic-reticulum; Cell-death; Protein; Glycoprotein; P53; Identification; Secretion
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Quellenangaben Band: 189, Heft: 17, Seiten: 5429-5448 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Network Biology (INET)
Förderungen NIAID NIH HHS
NINDS NIH HHS
NHGRI NIH HHS
NIGMS NIH HHS
Howard Hughes Medical Institute Funding Source: Medline