Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha |
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Authors: | Hetz Claudio Bernasconi Paula Fisher Jill Lee Ann-Hwee Bassik Michael C Antonsson Bruno Brandt Gabriel S Iwakoshi Neal N Schinzel Anna Glimcher Laurie H Korsmeyer Stanley J |
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Institution: | Howard Hughes Medical Institute, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA. chetz@hsph.harvard.edu |
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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. |
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