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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Autores principales:	Nicolas Menzel, Wolfgang Fischl, Kathrin Hueging, Dorothea Bankwitz, Anne Frentzen, Sibylle Haid, Juliane Gentzsch, Lars Kaderali, Ralf Bartenschlager, Thomas Pietschmann
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/60b449c1cbb44d7fa6971dd322b50980
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spelling	oai:doaj.org-article:60b449c1cbb44d7fa6971dd322b509802021-11-18T06:04:10ZMAP-kinase regulated cytosolic phospholipase A2 activity is essential for production of infectious hepatitis C virus particles.1553-73661553-737410.1371/journal.ppat.1002829https://doaj.org/article/60b449c1cbb44d7fa6971dd322b509802012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22911431/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Hepatitis 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.Nicolas MenzelWolfgang FischlKathrin HuegingDorothea BankwitzAnne FrentzenSibylle HaidJuliane GentzschLars KaderaliRalf BartenschlagerThomas PietschmannPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 7, p e1002829 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Nicolas Menzel Wolfgang Fischl Kathrin Hueging Dorothea Bankwitz Anne Frentzen Sibylle Haid Juliane Gentzsch Lars Kaderali Ralf Bartenschlager Thomas Pietschmann 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.
format	article
author	Nicolas Menzel Wolfgang Fischl Kathrin Hueging Dorothea Bankwitz Anne Frentzen Sibylle Haid Juliane Gentzsch Lars Kaderali Ralf Bartenschlager Thomas Pietschmann
author_facet	Nicolas Menzel Wolfgang Fischl Kathrin Hueging Dorothea Bankwitz Anne Frentzen Sibylle Haid Juliane Gentzsch Lars Kaderali Ralf Bartenschlager Thomas Pietschmann
author_sort	Nicolas Menzel
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.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/60b449c1cbb44d7fa6971dd322b50980
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MAP-kinase regulated cytosolic phospholipase A2 activity is essential for production of infectious hepatitis C virus particles.

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