NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis

Endoplasmic reticulum (ER)-induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus...

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Bibliographic Details
Published in:The Journal of cell biology 2010-12, Vol.191 (6), p.1113-1125
Main Authors: Li, Gang, Scull, Christopher, Ozcan, Lale, Tabas, Ira
Format: Article
Language:English
Subjects:
Animals
Annexins
Apoptosis
Atherosclerosis
Calcium
Cholesterols
eIF-2 Kinase - genetics
eIF-2 Kinase - metabolism
Endoplasmic Reticulum - metabolism
Kinases
Macrophages
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Messenger RNA
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Molecular biology
NADP - metabolism
NADPH Oxidase 2
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Oxidases
Oxidation
Oxidative stress
Oxidative Stress - physiology
Phosphates
Ribonucleic acid
RNA
Signal Transduction
Small interfering RNA
Transcription Factor CHOP - genetics
Transcription Factor CHOP - metabolism
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Summary:Endoplasmic reticulum (ER)-induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus on a previously elucidated ER stress-apoptosis pathway whose molecular components have been identified and documented to cause apoptosis in vivo. We now show that nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) and NOX-mediated oxidative stress are induced by this pathway and that apoptosis is blocked by both genetic deletion of the NOX subunit NOX2 and by the antioxidant N-acetylcysteine. Unexpectedly, NOX and oxidative stress further amplify CCAAT/enhancer binding protein homologous protein (CHOP) induction through activation of the double-stranded RNA-dependent protein kinase (PKR). In vivo, NOX2 deficiency protects ER-stressed mice from renal cell CHOP induction and apoptosis and prevents renal dysfunction. These data provide new insight into how ER stress, oxidative stress, and PKR activation can be integrated to induce apoptosis in a pathophysiologically relevant manner.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201006121