A research team led by Dr. Ruey-Hwa Chen, Distinguished Research Fellow at the Institute of Biological Chemistry, has discovered a ubiquitin-dependent mechanism in controlling the life-death cell fate in response to different cellular stresses. In addition, they have exploited this regulation to develop a novel anti-cancer therapeutic strategy. The research was recently published in Journal of Cell Biology.
BIK (BCL-2 interacting killer) is a potent inducer of a cell death program called apoptosis. Dr. Chen’s team identified that the Cul5-ASB11 ubiquitin ligase is responsible for BIK ubiquitination, which facilitates BIK degradation. Additionally, they found that the substrate binding subunit of this ubiquitin ligase, ASB11, is upregulated by ER stress and downregulated by DNA damage and both regulations are mediated by the IRE1a pathway. These opposite regulations of ASB11 dictate the cell life-death decision. Under DNA damage, BIK ubiquitination and degradation are decreased to facilitate an apoptotic cell fate. Conversely, ER stress-induced BIK ubiquitination and degradation prevent apoptosis to allow time for cell adaptation.
The research team further exploited this newly identified BIK regulation scheme to design a novel anti-cancer strategy. Gene therapy with the active BIK has been developed by Academician Mien-Chie Hung’s group as an anti-cancer strategy, which showed efficacy in multiple preclinical models of solid cancers. By collaborating with Academician Hung, the research team demonstrated that combined administration of the active BIK and an IRE1a inhibitor to block BIK degradation results in a synergistic tumor killing effect in cell and animal models. This finding offers a new promise for the clinical intervention of several devastating cancers, such as triple negative breast cancer and pancreatic cancer.
This study is funded by Academia Sinica Investigator Grant.
Article title: “BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress”
Web-linked to the published paper: https://doi.org/10.1083/jcb.201901156