+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor



The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor



Plos one 4(12): E8342



The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is reported to cause apoptosis of infected cells and several of its proteins including the 3a accessory protein, are pro-apoptotic. Since the 3a protein localizes to the endoplasmic reticulum (ER)-Golgi compartment, its role in causing ER stress was investigated in transiently transfected cells. Cells expressing the 3a proteins showed ER stress based on activation of genes for the ER chaperones GRP78 and GRP94. Since ER stress can cause differential modulation of the unfolded protein response (UPR), which includes the inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) pathways, these were individually tested in 3a-expressing cells. Only the PERK pathway was found to be activated in 3a-expressing cells based on (1) increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2alpha) and inhibitory effects of a dominant-negative form of eIF2alpha on GRP78 promoter activity, (2) increased translation of activating transcription factor 4 (ATF4) mRNA, and (3) ATF4-dependent activation of the C/EBP homologous protein (CHOP) gene promoter. Activation of PERK affects innate immunity by suppression of type 1 interferon (IFN) signaling. The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 056216387

Download citation: RISBibTeXText

PMID: 20020050


Related references

The coronavirus spike protein induces endoplasmic reticulum stress and upregulation of intracellular chemokine mRNA concentrations. Journal of Virology 81(20): 10981-10990, 2007

Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arteriosclerosis Thrombosis and Vascular Biology 32(7): 1687-1695, 2012

Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-delta-independent pathway in human colon cancer cells. Apoptosis 13(11): 1378-1385, 2008

Carbon monoxide induces heme oxygenase-1 via activation of protein kinase R-like endoplasmic reticulum kinase and inhibits endothelial cell apoptosis triggered by endoplasmic reticulum stress. Circulation Research 101(9): 919-927, 2007

Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress. American Journal of Physiology. Heart and Circulatory Physiology 288(5): H2381, 2005

SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. Plos Biology 6(9): E226, 2008

Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. Journal of Biological Chemistry 278(11): 9100-9106, 2003

Endoplasmic reticulum stress induces apoptosis by an apoptosome-dependent but caspase 12-independent mechanism. Journal of Biological Chemistry 281(5): 2693-2700, 2006

Differential sensitivities of severe acute respiratory syndrome (SARS) coronavirus spike polypeptide enzyme-linked immunosorbent assay (ELISA) and SARS coronavirus nucleocapsid protein ELISA for serodiagnosis of SARS coronavirus pneumonia. Journal of Clinical Microbiology 43(7): 3054-3058, 2005

Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis. Molecular Cancer Therapeutics 9(3): 718-730, 2010

Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum. Journal of Biological Chemistry 275(32): 24881-5, 2000

Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease. Molecular Genetics and Metabolism 107(3): 490-495, 2012

Interferon-gamma induces reactive oxygen species and endoplasmic reticulum stress at the hepatic apoptosis. Journal of Cellular Biochemistry 89(2): 244-253, 2003

Peroxisome Proliferator-activated Receptor g-independent Activation of p38 MAPK by Thiazolidinediones Involves Calcium/ Calmodulin-dependent Protein Kinase II and Protein Kinase R. Correlation With Endoplasmic Reticulum Stress. The Journal of Biological Chemistry 280(11): 109-18, 2005