12th International Conference on STRUCTURAL AND MOLECULAR BIOLOGY
Institute of Biological Chemistry-Academia Sinica, Taiwan
Title: Regulation of BIK ubiquitination determines life-death fate of cellular stress responses and anti-tumor activity
Biography: Ruey-Hwa Chen
The BH3-only pro-apoptotic protein BIK is regulated by ubiquitin-proteasome system. However, the underlying mechanism of this regulation and its physiological functions remain elusive. Here, we identify a BIK ubiquitination/degradation mechanism mediated by ubiquitin ligase Cul5ASB11. Under ER stress, ASB11 is transcriptionally activated by IRE1/XBP1 axis of unfolded protein responses, which results in an enhancement of BIK ubiquitination and proteolysis. Conversely, genotoxic agents act through p53 to down-regulate IRE1 and ASB11, thereby stabilizing BIK. These opposite regulations of ASB11-medaited BIK ubiquitination participate in part to the cell adaptation to ER stress and DNA damage-induced apoptosis. Finally, IRE1 inhibitors stabilize the active form of BIK and increase its anti-tumor efficacy in triple negative breast cancers. Together, our study identifies a BIK ubiquitin ligase, uncovers the opposite regulations of this BIK ubiquitination by ER stress and DNA damage, and exploits the targeting of BIK ubiquitination pathway combined with active BIK for cancer therapy.