title: 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-α, 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.
  
  
  OBJECTIVE
  The 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-α 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-α, 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.
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Center for Neurobiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors: Junsong
authors: J
authors: Zhang
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Department of Respiration, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors: Feng
authors: F
authors: Huang
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Likai
authors: L
authors: Tan
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Chuan
authors: C
authors: Bai
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Bing
authors: B
authors: Chen
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Jun
authors: J
authors: Liu
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Juanran
authors: J
authors: Liang
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Chao
authors: C
authors: Liu
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Shaoying
authors: S
authors: Zhang
authors: Department of Respiration, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors: Gen
authors: G
authors: Lu
authors: Center for Neurobiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors: Yuan
authors: Y
authors: Chen
authors: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China zhangh92@mail.sysu.edu.cn.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Hui
authors: H
authors: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D061985:Madin Darby Canine Kidney Cells; D019590:Nucleocapsid Proteins; D011485:Protein Binding; D020365:RNA Helicases / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; C530476:Mov10 protein, human; D012324:RNA-Dependent RNA Polymerase; D020365:RNA Helicases