title: Activation of the Nipah virus fusion protein in MDCK cells is mediated by cathepsin B within the endosome-recycling compartment.
abstract: Proteolytic activation of the fusion protein of the highly pathogenic Nipah virus (NiV F) is a prerequisite for the production of infectious particles and for virus spread via cell-to-cell fusion. Unlike other paramyxoviral fusion proteins, functional NiV F activation requires endocytosis and pH-dependent cleavage at a monobasic cleavage site by endosomal proteases. Using prototype Vero cells, cathepsin L was previously identified to be a cleavage enzyme. Compared to Vero cells, MDCK cells showed substantially higher F cleavage rates in both NiV-infected and NiV F-transfected cells. Surprisingly, this could not be explained either by an increased F endocytosis rate or by elevated cathepsin L activities. On the contrary, MDCK cells did not display any detectable cathepsin L activity. Though we could confirm cathepsin L to be responsible for F activation in Vero cells, inhibitor studies revealed that in MDCK cells, cathepsin B was required for F-protein cleavage and productive replication of pathogenic NiV. Supporting the idea of an efficient F cleavage in early and recycling endosomes of MDCK cells, endocytosed F proteins and cathepsin B colocalized markedly with the endosomal marker proteins early endosomal antigen 1 (EEA-1), Rab4, and Rab11, while NiV F trafficking through late endosomal compartments was not needed for F activation. In summary, this study shows for the first time that endosomal cathepsin B can play a functional role in the activation of highly pathogenic NiV.
authors.affiliation: Institute of Virology, Philipps University of Marburg, Marburg, Germanya; Faculty of Chemistry, University of Bielefeld, Bielefeld, Germany. maisner@staff.uni-marburg.de
authors.forename: Sandra
authors.initials: S
authors.lastname: Diederich
authors.forename: Lucie
authors.initials: L
authors.lastname: Sauerhering
authors.forename: Michael
authors.initials: M
authors.lastname: Weis
authors.forename: Hermann
authors.initials: H
authors.lastname: Altmeppen
authors.forename: Norbert
authors.initials: N
authors.lastname: Schaschke
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Stephanie
authors.initials: S
authors.lastname: Erbar
authors.forename: Andrea
authors.initials: A
authors.lastname: Maisner
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology* / Q000821:virology; D045464:Henipavirus Infections / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000821:virology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D045405:Nipah Virus / Q000235:genetics / Q000378:metabolism*; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014760:Viral Fusion Proteins; D002401:Cathepsin B; D056668:Cathepsin L