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.