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.