Abstract
Accumulation of misfolded protein in the endoplasmic reticulum (ER) triggers an adaptive stress response-termed the unfolded protein response (UPR)-mediated by the ER transmembrane protein kinase and endoribonuclease inositol-requiring enzyme-1alpha (IRE1alpha). We investigated UPR signaling events in mice in the absence of the proapoptotic BCL-2 family members BAX and BAK [double knockout (DKO)]. DKO mice responded abnormally to tunicamycin-induced ER stress in the liver, with extensive tissue damage and decreased expression of the IRE1 substrate X-box-binding protein 1 and its target genes. ER-stressed DKO cells showed deficient IRE1alpha signaling. BAX and BAK formed a protein complex with the cytosolic domain of IRE1alpha that was essential for IRE1alpha activation. Thus, BAX and BAK function at the ER membrane to activate IRE1alpha signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Animals
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Apoptosis*
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum / ultrastructure
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Endoplasmic Reticulum Chaperone BiP
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Endoribonucleases / metabolism*
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Gene Expression Regulation
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Heat-Shock Proteins / metabolism
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Humans
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Kidney / cytology
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Kidney / drug effects
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Kidney / metabolism
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Liver / cytology
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Liver / drug effects
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Liver / metabolism
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Mice
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Mice, Knockout
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Mitochondria / metabolism
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Molecular Chaperones / metabolism
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein Folding
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Recombinant Proteins / metabolism
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Regulatory Factor X Transcription Factors
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Signal Transduction
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Transcription Factor CHOP / metabolism
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Transcription Factors
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Tunicamycin / pharmacology
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bcl-2 Homologous Antagonist-Killer Protein / chemistry
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / metabolism*
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism*
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eIF-2 Kinase / metabolism
Substances
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Bak1 protein, mouse
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Bax protein, mouse
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DNA-Binding Proteins
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Endoplasmic Reticulum Chaperone BiP
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Heat-Shock Proteins
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Molecular Chaperones
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Nuclear Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins
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Regulatory Factor X Transcription Factors
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Transcription Factors
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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Tunicamycin
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Transcription Factor CHOP
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Ern1 protein, mouse
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Endoribonucleases