Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis.
Endoplasmic reticulum (ER) stress-induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-alpha (ER oxidase 1 alpha). In ER-stressed cells, ERO1-alpha is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-alpha suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-alpha or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-alpha in Chop(-/-) macrophages restores ER stress-induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop(-/-) mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-alpha-IP3R pathway.
Li
Gang
G
Department of Medicine, Columbia University, New York, NY 10032, USA.
Mongillo
Marco
M
Chin
King-Tung
KT
Harding
Heather
H
Ron
David
D
Marks
Andrew R
AR
Tabas
Ira
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007333:Insulin Resistance; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology / Q000473:pathology; D010088:Oxidoreductases; D034622:RNA Interference; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology
C497250:Ddit3 protein, mouse; D006023:Glycoproteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C491864:Ero1l protein, mouse; D010088:Oxidoreductases