Severe acute respiratory syndrome coronavirus envelope protein regulates cell stress response and apoptosis.
Severe acute respiratory syndrome virus (SARS-CoV) that lacks the envelope (E) gene (rSARS-CoV-ΔE) is attenuated in vivo. To identify factors that contribute to rSARS-CoV-ΔE attenuation, gene expression in cells infected by SARS-CoV with or without E gene was compared. Twenty-five stress response genes were preferentially upregulated during infection in the absence of the E gene. In addition, genes involved in signal transduction, transcription, cell metabolism, immunoregulation, inflammation, apoptosis and cell cycle and differentiation were differentially regulated in cells infected with rSARS-CoV with or without the E gene. Administration of E protein in trans reduced the stress response in cells infected with rSARS-CoV-ΔE or with respiratory syncytial virus, or treated with drugs, such as tunicamycin and thapsigargin that elicit cell stress by different mechanisms. In addition, SARS-CoV E protein down-regulated the signaling pathway inositol-requiring enzyme 1 (IRE-1) of the unfolded protein response, but not the PKR-like ER kinase (PERK) or activating transcription factor 6 (ATF-6) pathways, and reduced cell apoptosis. Overall, the activation of the IRE-1 pathway was not able to restore cell homeostasis, and apoptosis was induced probably as a measure to protect the host by limiting virus production and dissemination. The expression of proinflammatory cytokines was reduced in rSARS-CoV-ΔE-infected cells compared to rSARS-CoV-infected cells, suggesting that the increase in stress responses and the reduction of inflammation in the absence of the E gene contributed to the attenuation of rSARS-CoV-ΔE.
Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.
Marta L
ML
DeDiego
Jose L
JL
Nieto-Torres
Jose M
JM
Jiménez-Guardeño
Jose A
JA
Regla-Nava
Enrique
E
Alvarez
Juan Carlos
JC
Oliveros
Jincun
J
Zhao
Craig
C
Fett
Stanley
S
Perlman
Luis
L
Enjuanes
D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics* / Q000472:pathogenicity; D045169:Severe Acute Respiratory Syndrome / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism; D000086082:Viroporin Proteins; D014774:Virulence / Q000235:genetics; D014779:Virus Replication
C501689:E protein, SARS coronavirus; D014759:Viral Envelope Proteins; D000086082:Viroporin Proteins