Abstract 4605: CDIP-BAP31 complex bridges endoplasmic reticulum and mitochondria during ER-stress mediated apoptosis.

Abstract

Abstract Resolved ER stress response is fundamentally essential for intracellular homeostatic balance, but unsettled ER stress can lead to apoptosis. In addition, imbalances in homeostasis would result in improper cell functioning that may become an important pathogenic factor in a number of prevalent diseases, including neurodegenerative diseases, metabolic disorders, and cancers. However, the molecular mechanisms relating ER stress to apoptosis still remain largely unfamiliar. Here, we show that a proapoptotic p53 target, CDIP, acts as a key signal transducer of ER stress response. Applying a biochemical/proteomics approach, we characterize BAP31, B-cell receptor-associated protein 31 that is an integral protein of ER and known to crosstalk with mitochondrial proteins during the apoptosis process, as an interacting partner of CDIP. Upon ER stress, CDIP is induced and enhances an association with BAP31 at the ER membrane. We found that the CDIP-BAP31 complex formation is essential for ER stress-mediated apoptotic process. CDIP-/- or CDIP knock-down cells are strongly resistant to ER-stress-induced apoptosis. Moreover, we show that CDIP up-regulation and binding to BAP31 is required for BAP31 cleavage via caspase-8 activation in response to ER stress and also responsible for BAP31-Bcl-2 association, then resulting in Bcl-2 sequestration from BAX. The recruitment of Bcl-2 with BAP31-CDIP complex triggers BAX oligomerization/activation that causes its translocation to the mitochondria, followed by cyctochrome c release. Genetic knockout of CDIP in mice also leads to impaired response to ER-stress-mediated apoptosis, likely through reduced BAX activation. Together, our data demonstrate that the CDIP-BAP31→Bcl-2/BAX regulatory circuit represents a novel mechanism for establishing an ER-mitochondrial cross-talk for ER stress-mediated apoptosis signaling. Citation Format: Takushi Namba, Fang Tian, Kiki Chu, So-Young Hwang, Sam W. Lee. CDIP-BAP31 complex bridges endoplasmic reticulum and mitochondria during ER-stress mediated apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4605. doi:10.1158/1538-7445.AM2013-4605