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Poxvirus attack of anti-viral defense pathways unleashes an effector-triggered NF-κB response

Remick, B. C.; Mao, J. Q.; Manford, A. G.; Gutierrez-Jensen, A. D.; Wagner, A.; Rape, M.; McFadden, G.; Rahman, M. M.; Gaidt, M. M.; Vance, R. E.

2025-03-11 immunology
10.1101/2025.03.04.641538 bioRxiv
Show abstract

Effector-triggered immunity (ETI) is a form of pathogen sensing that involves detection of pathogen-encoded virulence factors or "effectors". To discover novel ETI pathways in mammals, we developed a screening approach in which individual virulence factors are expressed in human monocytes and transcriptional responses are assessed by RNA-seq. Using this approach, we identify a poxvirus effector, myxoma virus M3.1, which elicits an anti-viral NF-{kappa}B response. We find that NF-{kappa}B is unleashed by an ETI pathway that senses M3.1 attack of two anti-viral complexes: ZAP and TBK1. NF-{kappa}B activation occurs because the proteins inhibited by M3.1-- N4BP1, ZC3H12A, and TBK1--are negative regulators of NF-{kappa}B. Our results illustrate how negative regulators can function as pathogen sensors and establish a systematic approach for the discovery of ETI pathways.

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