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

The Journal of Cell Biology
Fei-Yun ChenRuey-Hwa Chen

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.

References

Jul 21, 2001·Molecular Cell·K Nakano, K H Vousden
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Matthew D Petroski, Raymond J Deshaies
Oct 10, 2006·FEBS Letters·Pedro J RealJose L Fernandez-Luna
Jul 3, 2007·Cell·Hamsa PuthalakathAndreas Strasser
Nov 10, 2007·Science·Jonathan H LinPeter Walter
Jan 20, 2009·Molecular Cell·Elinor DehanMichele Pagano
May 1, 2010·American Journal of Physiology. Gastrointestinal and Liver Physiology·Sophie C CazanaveGregory J Gores
Aug 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·Han LiPeter Walter
Dec 3, 2010·Biochimica Et Biophysica Acta·Diego RodriguezClaudio Hetz
Feb 2, 2011·Molecular Cancer Therapeutics·Yuh-Pyng SherMien-Chie Hung
Oct 21, 2011·Physiological Reviews·Claudio HetzLaurie H Glimcher
Nov 16, 2013·EMBO Reports·John R LydeardJ Wade Harper
Feb 4, 2014·Nature Communications·Hsin-Chieh WuRuey-Hwa Chen
Mar 19, 2014·The Journal of Cell Biology·Annamaria RuggianoPedro Carvalho
May 3, 2014·Molecular Cancer Therapeutics·Xiaoming XieMien-Chie Hung
Aug 26, 2014·Journal of Cell Science·Hemmo Meyer, Conrad C Weihl
Dec 9, 2014·Cell Cycle·Martin FischerKurt Engeland
Mar 31, 2015·Seminars in Cancer Biology·Marion MaurelAfshin Samali
Sep 28, 2015·Trends in Cell Biology·Dönem Avci, Marius K Lemberg

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Citations

Oct 11, 2020·Trends in Cell Biology·Matías González-QuirozRémy Pedeux
Oct 3, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Si-Wei XiaShi-Zhong Zheng

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Methods Mentioned

BETA
ubiquitination
GTPase
protein folding
immunoprecipitation
glycosylation
ChIP
ELISA
transfection
neddylation
PCR

Software Mentioned

Proteome Discoverer
MASCOT

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