BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress.
Bax inhibitor-1 (BI-1) is an evolutionarily conserved endoplasmic reticulum (ER) protein that suppresses cell death in both animal and plant cells. We characterized mice in which the bi-1 gene was ablated. Cells from BI-1-deficient mice, including fibroblasts, hepatocytes, and neurons, display selective hypersensitivity to apoptosis induced by ER stress agents (thapsigargin, tunicamycin, brefeldin A), but not to stimulators of mitochondrial or TNF/Fas-death receptor apoptosis pathways. Conversely, BI-1 overexpression protects against apoptosis induced by ER stress. BI-1-mediated protection from apoptosis induced by ER stress correlated with inhibition of Bax activation and translocation to mitochondria, preservation of mitochondrial membrane potential, and suppression of caspase activation. BI-1 overexpression also reduces releasable Ca(2+) from the ER. In vivo, bi-1(-/-) mice exhibit increased sensitivity to tissue damage induced by stimuli that trigger ER stress, including stroke and tunicamycin injection. Thus, BI-1 regulates a cell death pathway important for cytopreservation during ER stress.
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Han-Jung
HJ
Chae
Hyung-Ryong
HR
Kim
Chunyan
C
Xu
Beatrice
B
Bailly-Maitre
Maryla
M
Krajewska
Stan
S
Krajewski
Steven
S
Banares
Janice
J
Cui
Murat
M
Digicaylioglu
Ning
N
Ke
Shinichi
S
Kitada
Edward
E
Monosov
Michael
M
Thomas
Christina L
CL
Kress
Jeremy R
JR
Babendure
Roger Y
RY
Tsien
Stuart A
SA
Lipton
John C
JC
Reed
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
D008565:Membrane Proteins; C490015:Tmbim6 protein, mouse; D002118:Calcium