PMID:16645094

Citation	Hetz, C, Bernasconi, P, Fisher, J, Lee, AH, Bassik, MC, Antonsson, B, Brandt, GS, Iwakoshi, NN, Schinzel, A, Glimcher, LH and Korsmeyer, SJ (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312:572-6
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.
Links	PubMed Online version:10.1126/science.1123480
Keywords	Animals; Apoptosis; DNA-Binding Proteins/metabolism; Endoplasmic Reticulum/metabolism; Endoplasmic Reticulum/ultrastructure; Endoribonucleases/metabolism; Gene Expression Regulation; Heat-Shock Proteins/metabolism; Humans; Kidney/cytology; Kidney/drug effects; Kidney/metabolism; Liver/cytology; Liver/drug effects; Liver/metabolism; Mice; Mice, Knockout; Mitochondria/metabolism; Molecular Chaperones/metabolism; Nuclear Proteins/metabolism; Phosphorylation; Protein Folding; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; Recombinant Proteins/metabolism; Signal Transduction; Transcription Factor CHOP/metabolism; Transcription Factors; Tunicamycin/pharmacology; bcl-2 Homologous Antagonist-Killer Protein/chemistry; bcl-2 Homologous Antagonist-Killer Protein/genetics; bcl-2 Homologous Antagonist-Killer Protein/metabolism; bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism; eIF-2 Kinase/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:BAX	involved_in	GO:1900103: positive regulation of endoplasmic reticulum unfolded protein response	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:P17861)|has_direct_input(UniProtKB:O75460)	Seeded From UniProt	complete
HUMAN:BAX	involved_in	GO:0070059: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:BAK	involved_in	GO:1900103: positive regulation of endoplasmic reticulum unfolded protein response	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_at:(GO:0005789)	Seeded From UniProt	complete
HUMAN:ERN1	involved_in	GO:1900103: positive regulation of endoplasmic reticulum unfolded protein response	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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