Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

Bunyavirus ribonucleoprotein (RNP) that is assembled by polymerized nucleoproteins (N) coating a viral RNA and associating with a viral polymerase can be both the RNA synthesis machinery and the structural core of virions. Bunyaviral N and RNP thus could be assailable targets for host antiviral defense; however, it remains unclear which and how host factors target N/RNP to restrict bunyaviral infection. By mass spectrometry and protein-interaction analyses, we here show that host protein MOV10 targets the N proteins encoded by a group of emerging high-pathogenic representatives of bunyaviruses including severe fever with thrombocytopenia syndrome virus (SFTSV), one of the most dangerous pathogens listed by World Health Organization, in RNA-independent manner. MOV10 that was further shown to be induced specifically by SFTSV and related bunyaviruses in turn inhibits the bunyaviral replication in infected cells in series of loss/gain-of-function assays. Moreover, animal infection experiments with MOV10 knockdown corroborated the role of MOV10 in restricting SFTSV infection and pathogenicity in vivo. Minigenome assays and additional functional and mechanistic investigations demonstrate that the anti-bunyavirus activity of MOV10 is likely achieved by direct impact on viral RNP machinery but independent of its helicase activity and the cellular interferon pathway. Indeed, by its N-terminus, MOV10 binds to a protruding N-arm domain of N consisting of only 34 amino acids but proving important for N function and blocks N polymerization, N-RNA binding, and N-polymerase interaction, disabling RNP assembly. This study not only advances the understanding of bunyaviral replication and host restriction mechanisms but also presents novel paradigms for both direct antiviral action of MOV10 and host targeting of viral RNP machinery. Author summary Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging high-pathogenic bunyavirus listed by the World Health Organization as a top priority pathogen for research and development. Although SFTSV and related bunyaviruses emerging globally have raised serious public health concerns, specific antivirals or vaccines are currently unavailable and little is known on the virus-host interactions and viral replication mechanism. The nucleoprotein (N) is essential for bunyavirus replication by driving assembly of ribonucleoprotein (RNP), the RNA synthesis machinery and structural core of virions. Here we show that N proteins of SFTSV and related bunyaviruses can be targeted by host factor MOV10 in RNA-independent manner. Further, MOV10 can be induced specifically by the bunyaviruses and in turn restrict the viral replication and pathogenicity in vitro and in vivo. The anti-bunyavirus activity of MOV10 is independent of its helicase region and cellular interferon pathway. Instead, by its N-terminus, MOV10 binds to a protruding N-arm domain of N and blocks N polymerization, N-RNA binding, and N-polymerase interaction, disabling RNP assembly. This study provides a delicate model for host targeting of viral RNP machinery and sheds light on bunyaviral replication and host restriction mechanisms, which may promote specific antiviral therapy development.