# Poxvirus attack of antiviral defense pathways unleashes an effector-triggered NF-κB response

## TL;DR

The paper shows how a poxvirus protein triggers an immune response by attacking antiviral pathways in human cells.

## Contribution

A systematic approach for identifying effector-triggered immunity pathways in mammals using RNA-seq.

## Key findings

- The poxvirus effector M3.1 activates NF-κB by inhibiting antiviral complexes ZAP and TBK1.
- Negative regulators like N4BP1, ZC3H12A, and TBK1 are shown to play roles in immune sensing when inhibited.
- A new method for discovering ETI pathways was developed and successfully applied.

## Abstract

Effector-triggered immunity (ETI) is a form of pathogen sensing that involves detection of pathogen-encoded virulence factors or “effectors”. To discover ETI pathways in mammals, we developed a screening approach in which we expressed individual virulence factors in a human monocyte cell line and assessed transcriptional responses by RNA-seq. We identified a poxvirus effector, myxoma virus M3.1, which elicited an antiviral NF-κB response. NF-κB was unleashed by an ETI pathway that sensed M3.1 attack of two antiviral complexes: ZAP and TBK1. NF-κΒ activation occurred because the proteins inhibited by M3.1—N4BP1, ZC3H12A, and TBK1—are negative regulators of NF-κB. Our study established a systematic approach for the discovery of ETI pathways, and the results illustrated how negative regulators of immune responses may function in pathogen sensing.