title: Identification and characterization of three novel nuclear export signals in the influenza A virus nucleoprotein.
abstract: The nuclear export of the influenza A virus ribonucleoprotein (vRNP) is crucial for virus replication. As a major component of the vRNP, nucleoprotein (NP) alone can also be shuttled out of the nucleus by interacting with chromosome region maintenance 1 (CRM1) and is therefore hypothesized to promote the nuclear export of the vRNP. In the present study, three novel nuclear export signals (NESs) of the NP--NES1, NES2, and NES3--were identified as being responsible for mediating its nuclear export. The nuclear export of NES3 was CRM1 dependent, whereas that of NES1 or NES2 was CRM1 independent. Inactivation of these NESs led to an overall nuclear accumulation of NP. Mutation of all three NP-NESs significantly impaired viral replication. Based on structures of influenza virus NP oligomers, these three hydrophobic NESs are found present on the surface of oligomeric NPs. Functional studies indicated that oligomerization is also required for nuclear export of NP. Together, these results suggest that the nuclear export of NP is important for virus replication and relies on its NESs and oligomerization.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Maorong
authors.initials: M
authors.lastname: Yu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.forename: Shuai
authors.initials: S
authors.lastname: Cao
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.forename: Caiwei
authors.initials: C
authors.lastname: Chen
authors.forename: Shengyan
authors.initials: S
authors.lastname: Gao
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Bi
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.forename: Wenjun
authors.initials: W
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004285:Dogs; D015870:Gene Expression; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism*; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D049790:Nuclear Export Signals; D019590:Nucleocapsid Proteins; D055503:Protein Multimerization; D021381:Protein Transport; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014758:Viral Core Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D049790:Nuclear Export Signals; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014758:Viral Core Proteins; D000097606:Exportin 1 Protein; C048842:NP protein, Influenza A virus