SARS-CoV proteins decrease levels and activity of human ENaC via activation of distinct PKC isoforms

Autor: Weifeng Song, Sadis Matalon, Yong Jian Zhou, Hong Guang Nie, Xue Feng Su, Zhiqian Gao, Hong Long Ji, Albert Tousson, Yu Xian He, Ji-Bin Peng, Ying Liao, Yi Jiang
Rok vydání: 2009
Předmět:
Pulmonary and Respiratory Medicine
Epithelial sodium channel
Patch-Clamp Techniques
Physiology
Xenopus
Acute Lung Injury
Gene Expression
Pulmonary Edema
In Vitro Techniques
medicine.disease_cause
Transfection
Exocytosis
Cell Line
Viroporin Proteins
Amiloride
Viral Proteins
Viral Envelope Proteins
Physiology (medical)
medicine
Animals
Humans
Respiratory system
Epithelial Sodium Channels
Protein Kinase Inhibitors
Protein kinase C
Protein Kinase C
Coronavirus
Lung
Membrane Glycoproteins
biology
urogenital system
Cell Biology
Articles
respiratory system
Pulmonary edema
medicine.disease
Endocytosis
Recombinant Proteins
Enzyme Activation
Isoenzymes
Membrane glycoproteins
medicine.anatomical_structure
Severe acute respiratory syndrome-related coronavirus
Atypical pneumonia
Immunology
Spike Glycoprotein
Coronavirus
biology.protein
Oocytes
Female
Zdroj: American Journal of Physiology-Lung Cellular and Molecular Physiology
ISSN: 1522-1504
1040-0605
DOI: 10.1152/ajplung.90437.2008
Popis: 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 hypothesized that two of the hydrophilic structural coronoviral proteins (S and E) would 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. Coexpression of either S or E protein with human α-, β-, and γ-ENaC in Xenopus oocytes led to significant decreases of both amiloride-sensitive Na+currents and γ-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 α- or γ-ENaC were indentified. Instead, the downregulation of ENaC activity by SARS proteins was partially or completely restored by administration of inhibitors of PKCα/β1 and PKCζ. 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 PKCα/β1 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.
Databáze: OpenAIRE
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