title: Regulation of paramyxovirus fusion activation: the hemagglutinin-neuraminidase protein stabilizes the fusion protein in a pretriggered state.
abstract: The hemagglutinin (HA)-neuraminidase protein (HN) of paramyxoviruses carries out three discrete activities, each of which affects the ability of HN to promote viral fusion and entry: receptor binding, receptor cleaving (neuraminidase), and triggering of the fusion protein. Binding of HN to its sialic acid receptor on a target cell triggers its activation of the fusion protein (F), which then inserts into the target cell and mediates the membrane fusion that initiates infection. We provide new evidence for a fourth function of HN: stabilization of the F protein in its pretriggered state before activation. Influenza virus hemagglutinin protein (uncleaved HA) was used as a nonspecific binding protein to tether F-expressing cells to target cells, and heat was used to activate F, indicating that the prefusion state of F can be triggered to initiate structural rearrangement and fusion by temperature. HN expression along with uncleaved HA and F enhances the F activation if HN is permitted to engage the receptor. However, if HN is prevented from engaging the receptor by the use of a small compound, temperature-induced F activation is curtailed. The results indicate that HN helps stabilize the prefusion state of F, and analysis of a stalk domain mutant HN reveals that the stalk domain of HN mediates the F-stabilization effect.
authors.affiliation: Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA. map2028@med.cornell.edu
authors.forename: Matteo
authors.initials: M
authors.lastname: Porotto
authors.forename: Zuhair W
authors.initials: ZW
authors.lastname: Salah
authors.forename: Long
authors.initials: L
authors.lastname: Gui
authors.forename: Ilaria
authors.initials: I
authors.lastname: DeVito
authors.forename: Eric M
authors.initials: EM
authors.lastname: Jurgens
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Christine C
authors.initials: CC
authors.lastname: Yokoyama
authors.forename: Laura M
authors.initials: LM
authors.lastname: Palermo
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Lee
authors.forename: Anne
authors.initials: A
authors.lastname: Moscona
mesh_terms: D002460:Cell Line; D005434:Flow Cytometry; D015707:HN Protein / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D010222:Parainfluenza Virus 1, Human / Q000502:physiology*; D055550:Protein Stability; D011956:Receptors, Cell Surface / Q000378:metabolism; D013696:Temperature; D014760:Viral Fusion Proteins / Q000378:metabolism*; D053586:Virus Internalization; D001616:beta-Galactosidase
chemical_list: D015707:HN Protein; D011956:Receptors, Cell Surface; D014760:Viral Fusion Proteins; C092488:sialic acid receptor; D001616:beta-Galactosidase