La Crosse virus, but not Jamestown Canyon virus, is dependent on the host translation termination factor eRF1 due to changes in the nonstructural protein NSm

Bunyaviruses are a class of segmented, negative-sense RNA viruses that are transmitted by arthropod and rodent vectors. Members of the Orthobunyavirus genus and California Serogroup (CSG) circulate in the U.S., including La Crosse Virus (LACV), which is a leading cause of pediatric encephalitis. The host factors required for infection, particularly those that impact bunyavirus translation, are poorly understood. We found that host eukaryotic release factor 1 (eRF1) is important for viral infection; genetic depletion or pharmacological degradation of eRF1 inhibits LACV infection. eRF1 is the only cellular translation termination factor that binds stop codons on mRNAs and promotes the release of the nascent peptide from the ribosome. Surprisingly, we found that not all bunyaviruses rely on eRF1: two distantly related bunyaviruses in the Phenuiviridae family, Rift Valley fever virus and Punta Toro virus, were not sensitive to eRF1 inhibition. In contrast, three closely related CSG viruses—Snowshoe hare virus, California Encephalitis virus, and Tahyna virus—are dependent on eRF1. This led us to test a more distantly related CSG virus, Jamestown Canyon virus, which is in a distinct subgroup, and found that it is not sensitive to eRF1 depletion. Genetic analysis revealed that the non-structural M protein (NSm), encoded on the M segment of LACV, conferred sensitivity to eRF1. Together, these data present a previously unknown molecular requirement for a subset of orthobunyaviruses and show that LACV NSm drives viral dependency on eRF1. IMPORTANCE The California Serogroup (CSG) orthobunyavirus La Crosse virus (LACV) is the leading cause of arboviral pediatric encephalitis in the United States. Since there are no vaccines or therapeutics to treat LACV, we set out to identify host factors that promote infection as potential therapeutic targets. We found that host translation termination factor eRF1 is required for LACV infection and expected that this would be required for all bunyaviruses. While closely related CSG viruses were also dependent on eRF1, we found that eRF1 is dispensable for distantly related bunyaviruses. Surprisingly, Jamestown Canyon virus, another CSG virus, also does not depend on eRF1. This allowed us to use genetics to discover that the NSm protein sensitizes LACV to eRF1. This may represent a unique target for the treatment of LACV.