Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1a

Science 312, 572-576 (2006)

Speaker: 蔡志文                                                     Time: 14:00-15:00, June 7, 2006

Commentator: 劉校生 老師                                   Place: Room 601

Abstract:

        Endoplasmic reticulum (ER) is a network of folded membranes that extend through the cytoplasm to the nuclear membrane, and serves as a producing and processing station for proteins. Accumulation of unfolded or misfolded proteins in the ER lumen evokes specific signaling pathways, termed the unfolded protein response (UPR), to alter transcriptional and translational programs to cope with the ER stress.  This adaptive response stimulates UPR sensors IRE1a, PERK, and ATF6 and induces distinct pathways to recover cell homeostasis by decreasing the translation of misfolded protein, increasing the capacity of folding of unfolded protein, and eliminating the misfolded protein (1).  Previous study revealed that the double knockout (DKO) cells from BAX-BAK-deficient mice were resistant to apoptotic stimuli that induce the UPR (2).  In this paper, the authors found that the DKO mice responded abnormally to tunicamycin-induced ER stress in the liver, with extensive tissue damage and decreased expression of the IRE1a substrate, X-box-binding protein 1, and its target genes.  ER stress-induced IRE1a signaling was defective in the DKO cells.  Furthermore, BAX and BAK modulate IRE1a signaling through direct interaction of their BH1 and BH3 domains with the cytosolic domain of IRE1a.  Taken together, these results suggest that BAX and BAK function at the ER membrane to activate IRE1a signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.

References:

1.     Schroder, M. and Kaufman, R.J. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739-789 (2005).

2.     Wei, M.C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727-730 (2001).