Identification of GPx8 as a novel cellular substrate of the hepatitis C virus NS3-4A protease

Détails

ID Serval
serval:BIB_9CC0ABBC80F7
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Titre
Identification of GPx8 as a novel cellular substrate of the hepatitis C virus NS3-4A protease
Titre de la conférence
63rd Annual Meeting of the American Association for the Study of Liver Diseases
Auteur(s)
Morikawa K., Gouttenoire J., Tran H.T.L., Penin F., Heim M.H., Quadroni M., Moradpour D.
Adresse
Boston, United-States, November 9-13, 2012
ISBN
1527-3350
ISSN-L
0270-9139
Statut éditorial
Publié
Date de publication
2012
Volume
56
Série
Hepatology
Pages
707A
Langue
anglais
Notes
Document Type: Meeting Abstract
Résumé
Background: The hepatitis C virus (HCV) NS3-4A protease is
not only an essential component of the viral replication complex
and a prime target for antiviral intervention but also a key
player in the persistence and pathogenesis of HCV. It cleaves
and thereby inactivates two crucial adaptor proteins in viral
RNA sensing and innate immunity (MAVS and TRIF) as well as
a phosphatase involved in growth factor signaling (TC-PTP).
The aim of this study was to identify novel cellular substrates of
the NS3-4A protease and to investigate their role in the life
cycle and pathogenesis of HCV. Methods: Cell lines inducibly
expressing the NS3-4A protease were analyzed in basal as
well as interferon-
α
-stimulated states by stable isotopic labeling
using amino acids in cell culture (SILAC) coupled with protein
separation and mass spectrometry. Candidates fulfilling strin-
gent criteria for potential substrates or products of the NS3-4A
protease were further investigated in different experimental sys-
tems as well as in liver biopsies from patients with chronic hep-
atitis C. Results: SILAC coupled with protein separation and
mass spectrometry yielded > 5000 proteins of which 21 can-
didates were selected for further analyses. These allowed us to
identify GPx8, a membrane-associated peroxidase involved in
disulfide bond formation in the endoplasmic reticulum, as a
novel cellular substrate of the HCV NS3-4A protease. Cleavage
occurs at cysteine in position 11, removing the cytosolic tip of
GPx8, and was observed in different experimental systems as
well as in liver biopsies from patients with chronic hepatitis C.
Further functional studies, involving overexpression and RNA
silencing, revealed that GPx8 is a proviral factor involved in
viral particle production but not in HCV entry or RNA replica-
tion. Conclusions: GPx8 is a proviral host factor cleaved by the
HCV NS3-4A protease. Studies investigating the consequences
of cleavage for GPx8 function are underway. The identification
of novel cellular substrates of the HCV NS3-4A protease should
yield new insights into the HCV life cycle and the pathogenesis
of hepatitis C and may reveal novel angles for therapeutic inter-
vention.
Web of science
Création de la notice
14/02/2013 16:56
Dernière modification de la notice
20/08/2019 16:03
Données d'usage