title: Budding capability of the influenza virus neuraminidase can be modulated by tetherin.
abstract: We have determined that, in addition to its receptor-destroying activity, the influenza virus neuraminidase is capable of efficiently forming virus-like particles (VLPs) when expressed individually from plasmid DNA. This observation applies to both human subtypes of neuraminidase, N1 and N2. However, it is not found with every strain of influenza virus. Through gain-of-function and loss-of-function analyses, a critical determinant within the neuraminidase ectodomain was identified that contributes to VLP formation but is not sufficient to accomplish release of plasmid-derived VLPs. This sequence lies on the plasma membrane-proximal side of the neuraminidase globular head. Most importantly, we demonstrate that the antiviral restriction factor tetherin plays a role in determining the strain-specific limitations of release competency. If tetherin is counteracted by small interfering RNA knockdown or expression of the HIV anti-tetherin factor vpu, budding and release capability is bestowed upon an otherwise budding-deficient neuraminidase. These data suggest that budding-competent neuraminidase proteins possess an as-yet-unidentified means of counteracting the antiviral restriction factor tetherin and identify a novel way in which the influenza virus neuraminidase can contribute to virus release.
authors.affiliation: Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Department of Microbiology, Annenberg Bldg. 16-20, New York, NY 10128, USA. mark.yondola@mssm.edu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Yondola
authors.forename: Fiona
authors.initials: F
authors.lastname: Fernandes
authors.forename: Alan
authors.initials: A
authors.lastname: Belicha-Villanueva
authors.forename: Melissa
authors.initials: M
authors.lastname: Uccelini
authors.forename: Qinshan
authors.initials: Q
authors.lastname: Gao
authors.forename: Carol
authors.initials: C
authors.lastname: Carter
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D009439:Neuraminidase / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism*; D057074:Virus Release; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D009439:Neuraminidase; D014764:Viral Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C487630:NA protein, influenza A virus