MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles

Hepatitis C virus (HCV) has infected around 160 million individuals. Current therapies have limited efficacy and are fraught with side effects. To identify cellular HCV dependency factors, possible therapeutic targets, we manipulated signaling cascades with pathway-specific inhibitors. Using this ap...

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Main Authors:	Menzel, Nicolas, Fischl, Wolfgang, Hueging, Kathrin, Bankwitz, Dorothea, Frentzen, Anne, Haid, Sibylle, Gentzsch, Juliane, Kaderali, Lars, Bartenschlager, Ralf, Pietschmann, Thomas
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406102/

id	pubmed-3406102
recordtype	oai_dc
spelling	pubmed-34061022012-07-30 MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles Menzel, Nicolas Fischl, Wolfgang Hueging, Kathrin Bankwitz, Dorothea Frentzen, Anne Haid, Sibylle Gentzsch, Juliane Kaderali, Lars Bartenschlager, Ralf Pietschmann, Thomas Research Article Hepatitis C virus (HCV) has infected around 160 million individuals. Current therapies have limited efficacy and are fraught with side effects. To identify cellular HCV dependency factors, possible therapeutic targets, we manipulated signaling cascades with pathway-specific inhibitors. Using this approach we identified the MAPK/ERK regulated, cytosolic, calcium-dependent, group IVA phospholipase A2 (PLA2G4A) as a novel HCV dependency factor. Inhibition of PLA2G4A activity reduced core protein abundance at lipid droplets, core envelopment and secretion of particles. Moreover, released particles displayed aberrant protein composition and were 100-fold less infectious. Exogenous addition of arachidonic acid, the cleavage product of PLA2G4A-catalyzed lipolysis, but not other related poly-unsaturated fatty acids restored infectivity. Strikingly, production of infectious Dengue virus, a relative of HCV, was also dependent on PLA2G4A. These results highlight previously unrecognized parallels in the assembly pathways of these human pathogens, and define PLA2G4A-dependent lipolysis as crucial prerequisite for production of highly infectious viral progeny. Public Library of Science 2012-07-26 /pmc/articles/PMC3406102/ /pubmed/22911431 http://dx.doi.org/10.1371/journal.ppat.1002829 Text en Menzel et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Menzel, Nicolas Fischl, Wolfgang Hueging, Kathrin Bankwitz, Dorothea Frentzen, Anne Haid, Sibylle Gentzsch, Juliane Kaderali, Lars Bartenschlager, Ralf Pietschmann, Thomas
spellingShingle	Menzel, Nicolas Fischl, Wolfgang Hueging, Kathrin Bankwitz, Dorothea Frentzen, Anne Haid, Sibylle Gentzsch, Juliane Kaderali, Lars Bartenschlager, Ralf Pietschmann, Thomas MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles
author_facet	Menzel, Nicolas Fischl, Wolfgang Hueging, Kathrin Bankwitz, Dorothea Frentzen, Anne Haid, Sibylle Gentzsch, Juliane Kaderali, Lars Bartenschlager, Ralf Pietschmann, Thomas
author_sort	Menzel, Nicolas
title	MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles
title_short	MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles
title_full	MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles
title_fullStr	MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles
title_full_unstemmed	MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles
title_sort	map-kinase regulated cytosolic phospholipase a2 activity is essential for production of infectious hepatitis c virus particles
description	Hepatitis C virus (HCV) has infected around 160 million individuals. Current therapies have limited efficacy and are fraught with side effects. To identify cellular HCV dependency factors, possible therapeutic targets, we manipulated signaling cascades with pathway-specific inhibitors. Using this approach we identified the MAPK/ERK regulated, cytosolic, calcium-dependent, group IVA phospholipase A2 (PLA2G4A) as a novel HCV dependency factor. Inhibition of PLA2G4A activity reduced core protein abundance at lipid droplets, core envelopment and secretion of particles. Moreover, released particles displayed aberrant protein composition and were 100-fold less infectious. Exogenous addition of arachidonic acid, the cleavage product of PLA2G4A-catalyzed lipolysis, but not other related poly-unsaturated fatty acids restored infectivity. Strikingly, production of infectious Dengue virus, a relative of HCV, was also dependent on PLA2G4A. These results highlight previously unrecognized parallels in the assembly pathways of these human pathogens, and define PLA2G4A-dependent lipolysis as crucial prerequisite for production of highly infectious viral progeny.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406102/
_version_	1611545878370189312

MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles

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