Abstract
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 (eIF2α) and inhibitory effects of a dominant-negative form of eIF2α 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.
Highlights
A new virus, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), was responsible for an outbreak of acute respiratory illness in 2003, which affected about 30 countries with over 8000 cumulative infections and more than 900 deaths [1]
We looked at the transcriptional activation of grp78 and grp94 genes, which encode crucial endoplasmic reticulum (ER) chaperones that are markers of ER stress, in cells expressing the 3a protein
To rule out induction of ER stress merely due to over-expression of a viral protein, we studied the effects of the HIV proteins Nef and Vpu, and the hepatitis E virus (HEV) Orf3 protein, on grp78 and grp94 activation
Summary
A new virus, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), was responsible for an outbreak of acute respiratory illness in 2003, which affected about 30 countries with over 8000 cumulative infections and more than 900 deaths [1]. To adjust the biosynthetic burden and capacity of the ER for maintaining cellular homeostasis, the Unfolded Protein Response (UPR) is activated. The UPR is a complex pathway that is mediated by three distinct signaling tracks initiated by the sensors inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) [9]. These proteins transduce adaptive signals to the cytosol and nucleus, leading to global effects on ER function [10] and recovery from ER stress.
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