Cysteine Redox State Governs the Condensation Pathway of Hendra Virus W Protein and Differentially Impacts Type I IFN and NF‐κB Signaling

ABSTRACT The Hendra and Nipah viruses (HeV and NiV) are zoonotic biosafety level‐4 pathogens belonging to the Paramyxoviridae family. We previously showed that their W protein, a key player in the evasion of the host antiviral response, forms highly flexible, curved fibrils in vitro. Here, we show that the cysteine oxidation state acts as a molecular switch controlling the formation of either amorphous aggregates or flexible fibrils, and that residues 2 to 29 are essential for fibrillation. We also uncover that the HeV W protein (W ^HeV ) can also self‐assemble in cellula. W ^HeV forms distinct types of nuclear condensates that exhibit different dependencies on the cysteine redox state. While deletion of residues 2–29 prevents formation of nuclear filaments, cysteine‐to‐serine substitution mainly impairs the formation of non‐filamentous condensates. Both infection and W ^HeV ectopic expression trigger oxidative stress, presumably favorable to W ^HeV condensation. Finally, we show that impaired ability to form redox‐sensitive, non‐filamentous condensates is associated with a reduced W ability to inhibit the NF‐κB pathway, while it conversely enhances W ability to repress the interferon response pathway by enhancing W binding to STAT1.