BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress

Fei Yun Chen, Min Yu Huang, Yu Min Lin, Chi Huan Ho, Shu Yu Lin, Hsin Yi Chen, Mien Chie Hung, Ruey Hwa Chen

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin-proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α-XBP1s-ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.

Original languageEnglish
Pages (from-to)3002-3018
Number of pages17
JournalThe Journal of cell biology
Volume218
Issue number9
DOIs
Publication statusPublished - Sep 2 2019

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology

Cite this

Chen, F. Y., Huang, M. Y., Lin, Y. M., Ho, C. H., Lin, S. Y., Chen, H. Y., Hung, M. C., & Chen, R. H. (2019). BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress. The Journal of cell biology, 218(9), 3002-3018. https://doi.org/10.1083/jcb.201901156