Filter and export

Publications

What is a Publication?
3 Publications matching the given criteria: (Clear all filters)
Published year: 20093
The SARS Coronavirus 3a Protein Causes Endoplasmic Reticulum Stress and Induces Ligand-Independent Downregulation of the Type 1 Interferon Receptor

Abstract (Expand)

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 (eIF2a) and inhibitory effects of a dominant-negative form of eIF2a on GRP78 promoter activity, (2) increased translation of activating transcription factor 4 (ATF4) mRNA, and (3) ATF4dependent 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.

Authors: Rinki Minakshi, Kartika Padhan, Manjusha Rani, Nabab Khan, Faizan Ahmad, Shahid Jameel

Date Published: 17th Dec 2009

Publication Type: Journal

The ion channel activity of the SARS-coronavirus 3a protein is linked to its pro-apoptotic function

Abstract (Expand)

The severe acute respiratory syndrome-coronavirus (SARS-CoV) caused an outbreak of atypical pneumonia in 2003. The SARS-CoV viral genome encodes several proteins which have no homology to proteins in … any other coronaviruses, and a number of these proteins have been implicated in viral cytopathies. One such protein is 3a, which is also known as X1, ORF3 and U274. 3a expression is detected in both SARS-CoV infected cultured cells and patients. Among the different functions identified, 3a is a capable of inducing apoptosis. We previously showed that caspase pathways are involved in 3a-induced apoptosis. In this study, we attempted to find out protein domains on 3a that are essential for its pro-apoptotic function. Protein sequence analysis reveals that 3a possesses three major protein signatures, the cysteine-rich, Yxx␾ and diacidic domains. We showed that 3a proteins carrying respective mutations in these protein domains exhibit reduced pro-apoptotic activities, indicating the importance of these domains on 3a’s pro-apoptotic function. It was previously reported that 3a possesses potassium ion channel activity. We further demonstrated that the blockade of 3a’s potassium channel activity abolished caspase-dependent apoptosis. This report provides the first evidence that ion channel activity of 3a is required for its proapoptotic function. As ion channel activity has been reported to regulate apoptosis in different pathologic conditions, finding ways to modulate the ion channel activity may offer a new direction toward the inhibition of apoptosis triggered by SARS-CoV.

Authors: Chak-Ming Chan, Ho Tsoi, Wing-Man Chan, Shenyu Zhai, Ching-On Wong, Xiaoqiang Yao, Wood-Yee Chan, Stephen Kwok-Wing Tsui, Ho Yin Edwin Chan

Date Published: 1st Nov 2009

Publication Type: Journal

Coronaviruses post-SARS: update on replication and pathogenesis

Abstract

Not specified

Authors: Stanley Perlman, Jason Netland

Date Published: 1st Jun 2009

Publication Type: Journal

Powered by
 (v.1.16.2)
About FAIRDOMHub | Funding and Programmes | Credits | Terms & Conditions | Imprint | Cookie preferences
Copyright © 2008 - 2024 The University of Manchester and HITS gGmbH