title: Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin α1/β dimer of infected host cells.
abstract: The influenza A virus is a causative agent of influenza, which infects human cells and uses host factors to accomplish viral genome replication as part of its life cycle. The nucleoprotein (NP) and PB2 of the influenza virus associate with importin α1 to gain access to the host nucleus through a ternary import complex. Killer cell-mediated cytotoxicity is the primary mechanism of eliminating the influenza virus. Here, we showed that lymphokine-activated killer cells participated in the elimination of the influenza virus. Granzyme (Gzm) K inhibition elevated viral replication in vitro and aggravated viral infection in vivo. We identified that importin α1 and its transport partner protein importin β are physiological substrates of GzmK. Proteolysis of these two substrates wrecked their association to generate the importin α1/β dimer and disrupted transportation of viral NP to the nucleus, leading to inhibition of influenza virus replication.
authors.affiliation: CAS Key Laboratory of Infection and Immunity and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhong
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Toyoda
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.forename: Z
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002846:Chromatography, Affinity; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018613:Microscopy, Confocal; D009975:Orthomyxoviridae / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism*; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism*
chemical_list: D028901:alpha Karyopherins; D028961:beta Karyopherins; C087978:karyopherin alpha 2; D053804:Granzymes