title: DnaJA1/Hsp40 is co-opted by influenza A virus to enhance its viral RNA polymerase activity.
abstract: The RNA-dependent RNA polymerase (RdRp) of influenza A virus is a heterotrimeric complex composed of the PB1, PB2, and PA subunits. The interplay between host factors and the three subunits of the RdRp is critical to enable viral RNA synthesis to occur in the nuclei of infected cells. In this study, we newly identified host factor DnaJA1, a member of the type I DnaJ/Hsp40 family, acting as a positive regulator for influenza virus replication. We found that DnaJA1 associates with the bPB2 and PA subunits and enhances viral RNA synthesis both in vivo and in vitro. Moreover, DnaJA1 could be translocated from cytoplasm into the nucleus upon influenza virus infection. The translocation of DnaJA1 is specifically accompanied by PB1-PA nuclear import. Interestingly, we observed that the effect of DnaJA1 on viral RNA synthesis is mainly dependent on its C-terminal substrate-binding domain and not on its typical J domain, while the J domain normally mediates the Hsp70-DnaJ interaction required for regulating Hsp70 ATPase activity. Therefore, we propose that DnaJA1 is co-opted by the influenza A virus to enter the nucleus and to enhance its RNA polymerase activity in an Hsp70 cochaperone-independent manner.
  
  
  OBJECTIVE
  The interplay between host factors and influenza virus RNA polymerase plays a critical role in determining virus pathogenicity and host adaptation. In this study, we newly identified a host protein, DnaJA1/Hsp40, that is co-opted by influenza A virus RNA polymerase to enhance its viral RNA synthesis in the nuclei of infected cells. We found that DnaJA1 associates with both PB2 and PA subunits and translocates into the nucleus along with the nuclear import of the PB1-PA dimer during influenza virus replication. Interestingly, the effect of DnaJA1 is mainly dependent on its C-terminal substrate-binding domain and not on its typical J domain, which is required for its Hsp70 cochaperone function. To our knowledge, this is the first report on a member of the Hsp40s that is specifically involved in regulating influenza virus RNA polymerase. Targeting the interactions between polymerase subunits and DnaJA1 may provide a novel strategy to develop antiviral drugs.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Cao
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Candong
authors.initials: C
authors.lastname: Wei
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Qiannan
authors.initials: Q
authors.lastname: Jia
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China tao.deng@ipbcams.ac.cn zdsys@vip.sina.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China tao.deng@ipbcams.ac.cn zdsys@vip.sina.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Deng
mesh_terms: D002460:Cell Line; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000201:enzymology* / Q000502:physiology*; D012367:RNA, Viral / Q000096:biosynthesis; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D012367:RNA, Viral; D012324:RNA-Dependent RNA Polymerase