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Science 312 (5773): 572-576

Copyright © 2006 by the American Association for the Advancement of Science

Proapoptotic BAX and BAK Modulate the Unfolded Protein Response by a Direct Interaction with IRE1{alpha}

Claudio Hetz,1,2* Paula Bernasconi,1 Jill Fisher,1 Ann-Hwee Lee,2 Michael C. Bassik,1 Bruno Antonsson,4 Gabriel S. Brandt,5 Neal N. Iwakoshi,2 Anna Schinzel,1 Laurie H. Glimcher,2,3* Stanley J. Korsmeyer1{dagger}

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–1{alpha} (IRE1{alpha}). 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 IRE1{alpha} signaling. BAX and BAK formed a protein complex with the cytosolic domain of IRE1{alpha} that was essential for IRE1{alpha} activation. Thus, BAX and BAK function at the ER membrane to activate IRE1{alpha} signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.

1 Howard Hughes Medical Institute, Dana–Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
3 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
4 Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
5 Departments of Biochemistry and Chemistry, Rosenstiel Center, Brandeis University, Waltham, MA 02454, USA.

{dagger} Deceased.

* To whom correspondence should be addressed. E-mail: lglimche{at}hsph.harvard.edu (L.H.G.); chetz{at}hsph.harvard.edu. (C.H.)

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