Characterization of the Nucleocytoplasmic Shuttle of the Matrix Protein of Influenza B Virus

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Abstract
Influenza B virus is an enveloped negative-strand RNA virus that contributes considerably to annual influenza illnesses in human. The matrix protein of influenza B virus (BM1) acts as a cytoplasmic-nuclear shuttling protein during the early and late stages of infection. The mechanism of this intracellular transport of BM1 was revealed through the identification of two leucine-rich CRM1-dependent nuclear export signals (NESs) (3 to 14 amino acids [aa] and 124 to 133 aa), one bipartite nuclear localization signal (NLS) (76 to 94 aa), and two phosphorylation sites (80T and 84S) in BM1. The biological function of the NLS and NES regions were determined through the observation of the intracellular distribution of enhanced green fluorescent protein (EGFP)-tagged signal peptides, and wild-type, NES-mutant, and NLS-mutant EGFP-BM1. Furthermore, the NLS phosphorylation sites 80T and 84S, were found to be required for the nuclear accumulation of EGFP-NLS and for the efficient binding of EGFP-BM1 to human importin-α1. Moreover, all of these regions/sites were required for the generation of viable influenza B virus in a 12-plasmid virus rescue system. IMPORTANCE This study expands our understanding of the life cycle of influenza B virus by defining the dynamic mechanism of the nucleocytoplasmic shuttle of BM1 and could provide a scientific basis for the development of antiviral medication.