Sci. Aging Knowl. Environ., 3 May 2006
Vol. 2006, Issue 8, p. or10


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

Claudio Hetz, Paula Bernasconi, Jill Fisher, Ann-Hwee Lee, Michael C. Bassik, Bruno Antonsson, Gabriel S. Brandt, Neal N. Iwakoshi, Anna Schinzel, Laurie H. Glimcher, and Stanley J. Korsmeyer

Abstract: Science 312, 572-576 (2006).

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.

[Abstract/Full Text]

Science of Aging Knowledge Environment. ISSN 1539-6150