Noncanonical P gene mRNA editing in Cedar virus generates a V-like protein that is required for efficient virion production

Abstract Highly pathogenic Hendra and Nipah viruses encode accessory P gene products (C, V and W) that antagonize innate immunity and contribute to pathogenicity. Cedar virus (CedV), an apathogenic bat-borne henipavirus, is presumed to lack P gene mRNA editing and therefore is unable to express V and W proteins. Here, we identify CedV peptides originating from a frameshifted P gene open reading frame and demonstrate a previously unrecognized, noncanonical editing event at a homopolymeric adenine tract that introduces single-nucleotide A or G insertion. This mRNA editing produces a V-like protein whose C-terminal domain shares sequence and predicted structural features with those of the henipavirus V protein and displays cytoplasmic and nuclear localization. Recombinant CedV mutants defective in mRNA editing or with a truncated C-terminus were only recoverable by trans-complementation and showed markedly reduced release of infectious virus in cell culture and attenuated replication in mice lacking type I interferon receptor. Our data revise the CedV gene expression models and reveal a noncanonical editing mechanism that supports the production of a V-like protein critical for efficient infectious virus release. These results expand the fundamental concepts of paramyxovirus gene expression and reveal an unexpected, pivotal role for mRNA editing in virus egress, with direct implications for the evaluation of potentially high-consequence paramyxoviruses. Competing Interest Statement The authors have declared no competing interest. Footnotes author contributions updated; typo in line 549 corrected