title: A nuclear export signal in the matrix protein of Influenza A virus is required for efficient virus replication.
abstract: The influenza A virus matrix 1 protein (M1) shuttles between the cytoplasm and the nucleus during the viral life cycle and plays an important role in the replication, assembly, and budding of viruses. Here, a leucine-rich nuclear export signal (NES) was identified specifically for the nuclear export of the M1 protein. The predicted NES, designated the Flu-A-M1 NES, is highly conserved among all sequences from the influenza A virus subtype, but no similar NES motifs are found in the M1 sequences of influenza B or C viruses. The biological function of the Flu-A-M1 NES was demonstrated by its ability to translocate an enhanced green fluorescent protein (EGFP)-NES fusion protein from the nucleus to the cytoplasm in transfected cells, compared to the even nuclear and cytoplasmic distribution of EGFP. The translocation of EGFP-NES from the nucleus to the cytoplasm was not inhibited by leptomycin B. NES mutations in M1 caused a nuclear retention of the protein and an increased nuclear accumulation of NEP during transfection. Indeed, as shown by rescued recombinant viruses, the mutation of the NES impaired the nuclear export of M1 and significantly reduced the virus titer compared to titers of wild-type viruses. The NES-defective M1 protein was retained in the nucleus during infection, accompanied by a lowered efficiency of the nuclear export of viral RNPs (vRNPs). In conclusion, M1 nuclear export was specifically dependent on the Flu-A-M1 NES and critical for influenza A virus replication.
authors.affiliation: Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Cao
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.forename: Maorong
authors.initials: M
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Jia
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Bi
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
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; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D004285:Dogs; D006801:Humans; D009980:Influenza A virus / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D049790:Nuclear Export Signals; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D049790:Nuclear Export Signals; D014763:Viral Matrix Proteins