Host Protein Moloney Leukemia Virus 10 (MOV10) Acts as a Restriction Factor of Influenza A Virus by Inhibiting the Nuclear Import of the Viral Nucleoprotein

Abstract

The viral ribonucleoprotein (vRNP) complex of influenza A viruses (IAVs) contains an RNA-dependent RNA polymerase complex (RdRp) and nucleoprotein (NP) and is the functional unit for viral RNA transcription and replication. The vRNP complex is an important determinant of virus pathogenicity and host adaptation, implying that its function can be affected by host factors. In our study, we identified host protein Moloney leukemia virus 10 (MOV10) as an inhibitor of IAV replication, since depletion of MOV10 resulted in a significant increase in virus yield. MOV10 inhibited the polymerase activity in a minigenome system through RNA-mediated interaction with the NP subunit of vRNP complex. Importantly, we found that the interaction between MOV10 and NP prevented the binding of NP to importin-␣, resulting in the retention of NP in the cytoplasm. Both the binding of MOV10 to NP and its inhibitory effect on polymerase activity were independent of its helicase activity. These results suggest that MOV10 acts as an anti-influenza virus factor through specifically inhibiting the nuclear transportation of NP and subsequently inhibiting the function of the vRNP complex. IMPORTANCEThe interaction between the influenza virus vRNP complex and host factors is a major determinant of viral tropism and pathogenicity. Our study identified MOV10 as a novel host restriction factor for the influenza virus life cycle since it inhibited the viral growth rate. Conversely, importin-␣ has been shown as a determinant for influenza tropism and a positive regulator for viral polymerase activity in mammalian cells but not in avian cells. MOV10 disrupted the interaction between NP and importin-␣, suggesting that MOV10 could also be an important host factor for influenza virus transmission and pathogenicity. Importantly, as an interferon (IFN)-inducible protein, MOV10 exerted a novel mechanism for IFNs to inhibit the replication of influenza viruses. Furthermore, our study potentially provides a new drug design strategy, the use of molecules that mimic the antiviral mechanism of MOV10.

Influenza A Virus-induced expression of ISG20 inhibits viral replication by interacting with nucleoprotein

“…Human heat-shock protein 40 (Hsp40) and cytoskeleton-scaffolding protein alpha-actinin-4 interact with NP to promote viral replication [38,39]. Nevertheless, host protein Moloney leukemia virus 10 (MOV10) and tripartite motif protein superfamily member (TRIM22) interact with NP to inhibit viral replication [37,42]. The interaction between MOV10 and NP results in the retention of NP in the cytoplasm, and the inhibitory effect is independent on its helicase activity.…”

“…The polymerase complex is a critical component of the viral structure, and inhibition of the polymerase activity reflected the extensive effect of ISG20 on the viral life cycle. Several proteins and compounds inhibit IAV replication by reducing viral polymerase activity [35][36][37]. For instance, the multiple kinase inhibitor WV970 inhibits RNA expression and polymerase activity of IAV and was identified as a novel antiviral drug candidate [36].…”

“…NP is a multi-functional protein of IAV, and several host factors were identified to interact with NP, and the interaction between NP and host factors exhibited its diverse role in viral life cycle [37][38][39][40][41][42]. The human anti-apoptosis protein clusterin (CLU) is targeted by NP to induced apoptosis [41].…”

Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System

“…Later studies determined that MOV10 is able to reduce the infectivity of HIV-1, simian immunodeficiency virus, and murine leukemia virus (Wang et al, 2010). MOV10 is thought to multifunctional protein that MOV10 binds to polymerase basic protein 2 (PB2) in nucleoprotein (NP) of IAV and inhibits IAV replication which is unnecessary for RNA helicase activity (Zhang et al, 2016a).…”

Insights into Adenovirus Uncoating from Interactions with Integrins and Mediators of Host Immunity

“…Although such neutralization processes have not yet been identified with adenovirus, other viruses such as herpes simplex virus I [97] and influenza viruses [98,99] are susceptible to restriction by host factors that block viral nucleic acid transport or residence in the nucleus. Such discoveries have added new knowledge on the role of host cell responses to virus infection.…”