Molecular components of a cell death pathway activated by endoplasmic reticulum stress.
Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) cause ER stress that ultimately leads to programmed cell death. Recent studies have shown that ER stress triggers programmed cell death via an alternative intrinsic pathway of apoptosis that, unlike the intrinsic pathway described previously, is independent of Apaf-1 and cytochrome c. In the present work, we have used a set of complementary approaches, including two-dimensional gel electrophoresis coupled with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry and nano-liquid chromatography-electrospray ionization mass spectrometry with tandem mass spectrometry, RNA interference, co-immunoprecipitation, immunodepletion of candidate proteins, and reconstitution studies, to identify mediators of the ER stress-induced cell death pathway. Our data identify two molecules, valosin-containing protein and apoptosis-linked gene-2 (ALG-2), that appear to play a role in mediating ER stress-induced cell death.
Rao
Rammohan V
RV
The Buck Institute for Age Research, Novato, California 94945, USA.
Poksay
Karen S
KS
Castro-Obregon
Susana
S
Schilling
Birgit
B
Row
Richard H
RH
del Rio
Gabriel
G
Gibson
Bradford W
BW
Ellerby
H Michael
HM
Bredesen
Dale E
DE
D017209:Apoptosis / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002458:Cell Fractionation; D002460:Cell Line; D002474:Cell-Free System; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008861:Microsomes / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013314:Stress, Mechanical; D019284:Thapsigargin / Q000494:pharmacology
D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019284:Thapsigargin; D008156:Luciferases