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

Abstract

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.

CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

“…Overexpression of MOV10 also inhibits replication and reduces infectivity of a wide range of exogenous retroviruses, including human immunodeficiency virus type-1 (HIV-1) [35,[42][43][44][45]. Furthermore, MOV10 is an interferon-stimulated gene [46,47], which exhibits broad antiviral activity [46,[48][49][50][51][52][53][54][55]. Apart from retrotransposon restricting and antiviral activities, MOV10 has an essential role in post-transcriptional gene regulation, especially in the microRNA (miRNA) pathway [56][57][58][59].…”

MOV10 Helicase Interacts with Coronavirus Nucleocapsid Protein and Has Antiviral Activity

“…Both proviral and antiviral functions have been reported for MOV10. It is required for hepatitis delta virus (HDV) replication but not for the translation of its mRNA ( 37 ), facilitates enterovirus replication ( 38 ), inhibits replication of HIV-1 and other retroviruses at multiple steps ( 39 ), inhibits nuclear import of influenza virus nucleoprotein ( 40 ), inhibits porcine reproductive and respiratory syndrome virus (PRRSV) replication by avoiding nucleocapsid protein trafficking to the nucleus ( 41 ), inhibits hepatitis C virus (HCV) and dengue virus replication by partly unknown mechanisms ( 42 , 43 ), and inhibits bunyavirus replication by blocking several nucleoprotein functions ( 44 ). In the case of hepatitis B virus (HBV), contradictory data have been reported for both its proviral ( 45 ) and antiviral ( 46 ) activities.…”

Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

“…The role of MOV10 during bunyaviral infections was only recently studied [ 101 ]. It was shown that SFTSV infection specifically upregulates MOV10 expression in vitro and that MOV10 inhibits the replication of SFTSV and other related viruses (Heartland virus (HRTV) and Guertu virus (GTV)) in infected cells.…”