Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction.
Endoplasmic reticulum (ER) stress is linked to several pathological conditions including age-related macular degeneration. Excessive ER stress initiates cell death cascades which are mediated, in part, through mitochondrial dysfunction. Here, we identify αB crystallin as an important regulator of ER stress-induced cell death. Retinal pigment epithelial (RPE) cells from αB crystallin (-/-) mice, and human RPE cells transfected with αB crystallin siRNA, are more vulnerable to ER stress induced by tunicamycin. ER stress-mediated cell death is associated with increased levels of reactive oxygen species, depletion of glutathione in mitochondria, decreased superoxide dismutase activity, increased release of cytochrome c, and activation of caspases 3 and 4. The ER stress signaling inhibitors, salubrinal and 4-(2-aminoethyl) benzenesulfonyl fluoride, decrease mitochondrial damage and reduce RPE apoptosis induced by ER stress. Prolonged ER stress decreases levels of αB crystallin, thus exacerbating mitochondrial dysfunction. Overexpression of αB crystallin protects RPE cells from ER stress-induced apoptosis by attenuating increases in Bax, CHOP, mitochondrial permeability transition, and cleaved caspase 3. Thus, these data collectively demonstrate that αB crystallin provides critical protection of mitochondrial function during ER stress-induced RPE apoptosis.
Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo Street, Los Angeles, CA 90033, USA.
Guorui
G
Dou
Parameswaran G
PG
Sreekumar
Christine
C
Spee
Shikun
S
He
Stephen J
SJ
Ryan
Ram
R
Kannan
David R
DR
Hinton
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000378:metabolism
D002934:Cinnamates; D012333:RNA, Messenger; D013450:Sulfones; D038203:alpha-Crystallin B Chain; C496827:salubrinal; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D013890:Thiourea