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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
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2012-07
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Abstract
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.
Citation
MAP-Kinase Regulated Cytosolic Phospholipase A2 Activity Is Essential for Production of Infectious Hepatitis C Virus Particles. 2012, 8 (7):e1002829 PLoS Pathog.
Affiliation
Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
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PLoS pathogens
URI
http://hdl.handle.net/10033/247012
DOI
10.1371/journal.ppat.1002829
PubMed ID
22911431
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Article
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en
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1553-7374
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publications of the work group experimental Virology([TC]EVIR)