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

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 (WHeV) can also self-assemble in cellula. WHeV 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 WHeV ectopic expression trigger oxidative stress, presumably favorable to WHeV 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.