title: Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation.
abstract: The molecular mechanisms governing severe acute respiratory syndrome coronavirus-induced pathology are not fully understood. Virus infection and some individual viral proteins, including the 3a protein, induce apoptosis. However, the cellular targets leading to 3a protein-mediated apoptosis have not been fully characterized. This study showed that the 3a protein modulates the mitochondrial death pathway in two possible ways. Activation of caspase-8 through extrinsic signal(s) caused Bid activation. In the intrinsic pathway, there was activation of caspase-9 and cytochrome c release from the mitochondria. This was the result of increased Bax oligomerization and higher levels of p53 in 3a protein-expressing cells, which depended on the activation of p38 MAP kinase (MAPK) in these cells. For p38 activation and apoptosis induction, the 3a cytoplasmic domain was sufficient. In direct Annexin V staining assays, the 3a protein-expressing cells showed increased apoptosis that was attenuated with the p38 MAPK inhibitor SB203580. A block in nuclear translocation of the STAT3 transcription factor in cells expressing the 3a protein was also observed. These results have been used to present a model of 3a-mediated apoptosis.
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
authors.forename: Kartika
authors.initials: K
authors.lastname: Padhan
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
authors.forename: Rinki
authors.initials: R
authors.lastname: Minakshi
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
authors.forename: Mohammad Aatif Bin
authors.initials: MAB
authors.lastname: Towheed
authors.affiliation: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
authors.forename: Shahid
authors.initials: S
authors.lastname: Jameel
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000378:metabolism / Q000472:pathogenicity*; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000378:metabolism*; D000086082:Viroporin Proteins; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C487105:3a protein, SARS-CoV; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D000086082:Viroporin Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580