title: Cyclophilin E functions as a negative regulator to influenza virus replication by impairing the formation of the viral ribonucleoprotein complex.
abstract: BACKGROUND
  The nucleoprotein (NP) of influenza A virus is a multifunctional protein that plays a critical role in the replication and transcription of the viral genome. Therefore, examining host factors that interact with NP may shed light on the mechanism of host restriction barriers and the tissue tropism of influenza A virus. Here, Cyclophilin E (CypE), a member of the peptidyl-propyl cis-trans isomerase (PPIase) family, was found to bind to NP and inhibit viral replication and transcription.
  
  
  RESULTS
  In the present study, CypE was found to interact with NP but not with the other components of the viral ribonucleoprotein complex (VRNP): PB1, PB2, and PA. Mutagenesis data revealed that the CypE domain comprised of residues 137-186 is responsible for its binding to NP. Functional analysis results indicated that CypE is a negative regulator in the influenza virus life cycle. Furthermore, knock-down of CypE resulted in increased levels of three types of viral RNA, suggesting that CypE negatively affects viral replication and transcription. Moreover, up-regulation of CypE inhibited the activity of influenza viral polymerase. We determined that the molecular mechanism by which CypE negatively regulates influenza virus replication and transcription is by interfering with NP self-association and the NP-PB1 and NP-PB2 interactions.
  
  
  CONCLUSIONS
  CypE is a host restriction factor that inhibits the functions of NP, as well as viral replication and transcription, by impairing the formation of the vRNP. The data presented here will help us to better understand the molecular mechanisms of host restriction barriers, host adaptation, and tissue tropism of influenza A virus.
authors: Center for Molecular Virology, Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: Zengfu
authors: Z
authors: Wang
authors: Xiaoling
authors: X
authors: Liu
authors: Zhendong
authors: Z
authors: Zhao
authors: Chongfeng
authors: C
authors: Xu
authors: Ke
authors: K
authors: Zhang
authors: Caiwei
authors: C
authors: Chen
authors: Lei
authors: L
authors: Sun
authors: George F
authors: GF
authors: Gao
authors: Xin
authors: X
authors: Ye
authors: Wenjun
authors: W
authors: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D002645:Chickens; D021983:Cyclophilins / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D007251:Influenza, Human / Q000378:metabolism / Q000821:virology; D046912:Multiprotein Complexes / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012367:RNA, Viral / Q000378:metabolism; D012261:Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D046912:Multiprotein Complexes; D012367:RNA, Viral; D012261:Ribonucleoproteins; D014764:Viral Proteins; D021983:Cyclophilins; C114522:PPIE protein, human