Among the multiple organ disorders caused by the severe acute respiratory syndrome coronavirus (SARS-CoV), acute lung failure following atypical pneumonia is the most serious and often fatal event. We hypothesize that two of the hydrophilic structural coronoviral proteins (S and E) regulate alveolar fluid clearance by decreasing the cell surface expression and activity of amiloride-sensitive epithelial sodium (Na⁺) channels (ENaC), the rate limiting protein in transepithelial Na⁺ vectorial transport across distal lung epithelial cells. Co-expression of either S or E protein with human , and -ENaC in Xenopus oocytes led to significant decreases of both amiloride-sensitive Na⁺ currents and -ENaC protein levels at their plasma membranes, S and E proteins decreased the rate of ENaC exocytosis and either had no effect (S) or decreased (E) rates of endocytosis. No direct interactions among SARS-CoV E protein with either - or -ENaC were indentified. Instead, the down-regulation of ENaC activity by SARS proteins was partially or completely restored by administration of inhibitors of PKC/1 and PKC. Consistent with the whole-cell data, expression of S and E proteins decreased ENaC single channel activity in oocytes and these effects were partially abrogated by PKC/1 inhibitors. Finally transfection of human airway epithelial (H441) cells with SARS E protein decreased whole-cell amiloride-sensitive currents. These findings indicate that lung edema in SARS infection may be due at least in part to activation of PKC by SARS proteins leading to decreasing levels and activity of ENaC at the apical surfaces of lung epithelial cells.