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Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins.
Grant SN
,
Lester HA
.
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Severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS-CoV-2), which causes the coronavirus disease 2019, encodes several proteins whose roles are poorly understood. We tested their ability either to directly form plasma membrane ion channels or to change functions of two mammalian plasma membrane ion channels, the epithelial sodium channel (ENaC) and the α3β4 nicotinic acetylcholine receptor. In mRNA-injected Xenopus oocytes, none of nine SARS-CoV-2 proteins or two SARS-CoV-1 proteins produced conductances, nor did co-injection of several combinations. Immunoblots for ORF8, spike (S), and envelope (E) proteins revealed that the proteins are expressed at appropriate molecular weights. In experiments on coexpression with ENaC, three tested SARS proteins (SARS-CoV-1 E, SARS-CoV-2 E, and SARS-CoV-2 S) markedly decrease ENaC currents. SARS-CoV-1 S protein decreases ENaC currents modestly. Coexpressing the E proteins but not the S proteins with α3β4 nicotinic acetylcholine receptors significantly reduces acetylcholine-induced currents. ENaC inhibition does not occur if the SARS-CoV protein mRNAs are injected 24 h after the ENaC mRNAs, suggesting that SARS-CoV proteins affect early step(s) in functional expression of channel proteins. Consistent with the hypothesis that the SARS-CoV-2 S protein-induced ENaC inhibition involves competition for available protease, mutating the furin cleavage site in SARS-CoV-2 S protein partially relieves inhibition of ENaC currents. Extending previous suggestions that SARS proteins affect ENaC currents via protein kinase C (PKC) activation, PKC activation via phorbol 12-myristate 13-acetate decreases ENaC and α3β4 activity. Phorbol 12-myristate 13-acetate application reduced membrane capacitance ∼5%, presumably via increased endocytosis, but this decrease is much smaller than the SARS proteins' effects on conductances. Also, incubating oocytes in Gö-6976, a PKCα and PKCβ inhibitor, did not alter E or S protein-induced channel inhibition. We conclude that SARS-CoV-1 and SARS-CoV-2 proteins alter the function of human plasma membrane channels, via incompletely understood mechanisms. These interactions may play a role in the coronavirus 2019 pathophysiology.
Alvi,
Regulation of membrane trafficking and endocytosis by protein kinase C: emerging role of the pericentrion, a novel protein kinase C-dependent subset of recycling endosomes.
2007, Pubmed
Alvi,
Regulation of membrane trafficking and endocytosis by protein kinase C: emerging role of the pericentrion, a novel protein kinase C-dependent subset of recycling endosomes.
2007,
Pubmed
Anand,
SARS-CoV-2 strategically mimics proteolytic activation of human ENaC.
2020,
Pubmed
Blom,
Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor.
2019,
Pubmed
,
Xenbase
Cabrera-Garcia,
The envelope protein of SARS-CoV-2 increases intra-Golgi pH and forms a cation channel that is regulated by pH.
2021,
Pubmed
,
Xenbase
Castaño-Rodriguez,
Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis.
2018,
Pubmed
Chen,
Emerging coronaviruses: Genome structure, replication, and pathogenesis.
2020,
Pubmed
Chen,
Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation.
1998,
Pubmed
Cohen,
Identification of a Golgi complex-targeting signal in the cytoplasmic tail of the severe acute respiratory syndrome coronavirus envelope protein.
2011,
Pubmed
Delorey,
COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.
2021,
Pubmed
Dey,
In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) protein ion channel inhibitor.
2020,
Pubmed
Farag,
Viroporins and inflammasomes: A key to understand virus-induced inflammation.
2020,
Pubmed
Fronius,
Treatment of pulmonary edema by ENaC activators/stimulators.
2013,
Pubmed
Gentzsch,
A Pathophysiological Model for COVID-19: Critical Importance of Transepithelial Sodium Transport upon Airway Infection.
2020,
Pubmed
Gordon,
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
2020,
Pubmed
Gordon,
Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
2020,
Pubmed
Guzzi,
Master Regulator Analysis of the SARS-CoV-2/Human Interactome.
2020,
Pubmed
Harris,
Preferential assembly of epithelial sodium channel (ENaC) subunits in Xenopus oocytes: role of furin-mediated endogenous proteolysis.
2008,
Pubmed
,
Xenbase
Henderson,
Menthol Stereoisomers Exhibit Different Effects on α4β2 nAChR Upregulation and Dopamine Neuron Spontaneous Firing.
2018,
Pubmed
,
Xenbase
Hoffmann,
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.
2020,
Pubmed
Ji,
SARS-CoV proteins decrease levels and activity of human ENaC via activation of distinct PKC isoforms.
2009,
Pubmed
,
Xenbase
Kumar,
SARS-CoV-2-specific virulence factors in COVID-19.
2021,
Pubmed
Lin-Moshier,
A rapid Western blotting protocol for the Xenopus oocyte.
2013,
Pubmed
,
Xenbase
Martiny-Baron,
Selective inhibition of protein kinase C isozymes by the indolocarbazole Gö 6976.
1993,
Pubmed
Mazzo,
Nicotine-modulated subunit stoichiometry affects stability and trafficking of α3β4 nicotinic receptor.
2013,
Pubmed
Melms,
A molecular single-cell lung atlas of lethal COVID-19.
2021,
Pubmed
Mulay,
SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery.
2021,
Pubmed
Ng,
Proliferative growth of SARS coronavirus in Vero E6 cells.
2003,
Pubmed
Raikwar,
Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel.
2008,
Pubmed
Richter,
The recruitment of membrane-bound mRNAs for translation in microinjected Xenopus oocytes.
1983,
Pubmed
,
Xenbase
Sarkar,
Structural insight into the role of novel SARS-CoV-2 E protein: A potential target for vaccine development and other therapeutic strategies.
2020,
Pubmed
Shang,
Structural basis of receptor recognition by SARS-CoV-2.
2020,
Pubmed
Shimbo,
Viral and cellular small integral membrane proteins can modify ion channels endogenous to Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Szabó,
Hypothetical dysfunction of the epithelial sodium channel may justify neurohumoral blockade in coronavirus disease 2019.
2021,
Pubmed
To,
Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins.
2018,
Pubmed
Tong,
Tyrosine decaging leads to substantial membrane trafficking during modulation of an inward rectifier potassium channel.
2001,
Pubmed
,
Xenbase
Torres,
Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?
2015,
Pubmed
Valtueña,
Acral edema during the COVID-19 pandemic.
2020,
Pubmed
Vasilets,
Activation of protein kinase C by phorbol ester induces downregulation of the Na+/K(+)-ATPase in oocytes of Xenopus laevis.
1990,
Pubmed
,
Xenbase
Wang,
Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
1993,
Pubmed
,
Xenbase
Wolff,
A molecular pore spans the double membrane of the coronavirus replication organelle.
2020,
Pubmed
Wrapp,
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.
2020,
Pubmed
Yan,
Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.
2020,
Pubmed
Zhang,
The ORF4a protein of human coronavirus 229E functions as a viroporin that regulates viral production.
2014,
Pubmed
,
Xenbase
Zwaveling,
Pulmonary edema in COVID-19: Explained by bradykinin?
2020,
Pubmed
