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 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.
Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Nicolas
N
Menzel
Wolfgang
W
Fischl
Kathrin
K
Hueging
Dorothea
D
Bankwitz
Anne
A
Frentzen
Sibylle
S
Haid
Juliane
J
Gentzsch
Lars
L
Kaderali
Ralf
R
Bartenschlager
Thomas
T
Pietschmann
D016718:Arachidonic Acid / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D003716:Dengue Virus / Q000254:growth & development; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018116:Vesiculovirus / Q000254:growth & development; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
D002070:Butadienes; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D016718:Arachidonic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human