Activation of the Nipah virus fusion protein in MDCK cells is mediated by cathepsin B within the endosome-recycling compartment.
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Activation of the Nipah virus fusion protein in MDCK cells is mediated by cathepsin B within the endosome-recycling compartment. / Diederich, Sandra; Sauerhering, Lucie; Weis, Michael; Altmeppen, Hermann C.; Schaschke, Norbert; Reinheckel, Thomas; Erbar, Stephanie; Maisner, Andrea.
in: J VIROL, Jahrgang 86, Nr. 7, 7, 2012, S. 3736-3745.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Activation of the Nipah virus fusion protein in MDCK cells is mediated by cathepsin B within the endosome-recycling compartment.
AU - Diederich, Sandra
AU - Sauerhering, Lucie
AU - Weis, Michael
AU - Altmeppen, Hermann C.
AU - Schaschke, Norbert
AU - Reinheckel, Thomas
AU - Erbar, Stephanie
AU - Maisner, Andrea
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Dogs
KW - Endocytosis
KW - Cell Line
KW - Cathepsin B/genetics/metabolism
KW - Cathepsin L/genetics/metabolism
KW - Endosomes/enzymology/virology
KW - Henipavirus Infections/enzymology/genetics/physiopathology/virology
KW - Nipah Virus/genetics/metabolism
KW - Viral Fusion Proteins/genetics/metabolism
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Dogs
KW - Endocytosis
KW - Cell Line
KW - Cathepsin B/genetics/metabolism
KW - Cathepsin L/genetics/metabolism
KW - Endosomes/enzymology/virology
KW - Henipavirus Infections/enzymology/genetics/physiopathology/virology
KW - Nipah Virus/genetics/metabolism
KW - Viral Fusion Proteins/genetics/metabolism
M3 - SCORING: Journal article
VL - 86
SP - 3736
EP - 3745
JO - J VIROL
JF - J VIROL
SN - 0022-538X
IS - 7
M1 - 7
ER -
