NSUN2-mediated epitranscriptomic and ubiquitin modulation of Nipah virus matrix protein reveals a dual-targeting antiviral strategy

Nipah virus (NiV) poses a significant public health threat due to its high mortality rate and the absence of approved treatments. Nonetheless, the host-virus interactions underlying its pathogenesis remain poorly understood. Here, we identified the 5-methylcytosine (m⁵C) methyltransferase NSUN2 as a critical host factor hijacked by NiV to facilitate replication via dual mechanisms. The viral matrix (M) protein stabilizes NSUN2 by inhibiting its proteasomal degradation. In turn, NSUN2 catalyzes m⁵C deposition on NiV RNAs, enhancing M RNA stability and protein expression. Simultaneously, NSUN2’s noncatalytic domain engages GNB2 as an adaptor to facilitate the recruitment of the E3 ubiquitin ligase TRIM28 to M, promoting M ubiquitination and consequent nuclear export for virion assembly. Targeting both pathways using the proteasome inhibitor carfilzomib and the m⁵C inhibitor MY-1B suppressed NiV replication in vitro and in hamsters. Our findings uncover a dual epigenetic-posttranslational regulatory axis exploited by NiV and present a promising combinatorial therapeutic approach.