Enhanced Ca2+ leak from ER Ca2+ stores induced by hepatitis C NS5A protein.
The hepatitis C non-structural protein 5A (NS5A) is a Zn(2+)-binding phosphoprotein essential for viral replication. Expression of NS5A perturbs intracellular Ca(2+) levels by an undefined mechanism, activating transcription factors implicated in the chronic pathogenesis of hepatitis infections. Here, we demonstrate that regulated expression of NS5A enhanced the passive leak of Ca(2+) from a subset of the endoplasmic reticulum (ER) Ca(2+) stores. This action was not replicated by expression of the amphipathic NH(2)-membrane anchoring domain of NS5A alone, despite targeting to intracellular membranes. Depletion of the NS5A-targeted ER Ca(2+) store was prevented under conditions of ample ATP supply suggesting compensatory Ca(2+) ATPase activity, but observed under conditions of ATP insufficiency and in intact cells expressing NS5A.
Robinson
Lisbeth C
LC
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Marchant
Jonathan S
JS
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
D002118:Calcium; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase