An endoplasmic reticulum-specific stress-activated caspase (caspase-12) is implicated in the apoptosis of A549 epithelial cells by respiratory syncytial virus.
Respiratory syncytial virus (RSV) infection induced programmed cell death or apoptosis in the cultured lung epithelial cell line, A549. The apoptotic cells underwent multiple changes, including fragmentation and degradation of genomic DNA, consistent with the activation of the DNA fragmentation factor or caspase-activated DNase (DFF or CAD). The infection led to activation of FasL; however, a transdominant mutant of FAS-downstream death domain protein, FADD, did not inhibit apoptosis. Similarly, modest activation of cytoplasmic apoptotic caspases, caspase-3 and -8, were observed; however, only a specific inhibitor of caspases-3 inhibited apoptosis, while an inhibitor of caspase-8 had little effect. No activation of caspase-9 and -10, indicators of the mitochondrial apoptotic pathway, was observed. In contrast, RSV infection strongly activated caspase-12, an endoplasmic reticulum (ER) stress response caspase. Activation of the ER stress response was further evidenced by upregulation of ER chaperones BiP and calnexin. Antisense-mediated inhibition of caspase-12 inhibited apoptosis. Inhibitors of NF-kappa B had no effect on apoptosis. Thus, RSV-induced apoptosis appears to occur through an ER stress response that activates caspase-12, and is uncoupled from NF-kappa B activation.
Bitko
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Department of Biochemistry and Molecular Biology, MSB 2370, University of South Alabama, College of Medicine, Mobile, AL 36688-0002, USA.
Barik
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D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000821:virology; D006801:Humans; D020287:In Situ Nick-End Labeling; D016376:Oligonucleotides, Antisense / Q000235:genetics; D018384:Oxidative Stress; D010957:Plasmids; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D014162:Transfection
D017931:DNA Primers; D016376:Oligonucleotides, Antisense; C506444:CASP12 protein, human; D053454:Caspase 12; D020169:Caspases