Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
J Cell Biol. 2019 Sep 2;218(9):3002-3018. doi: 10.1083/jcb.201901156. Epub 2019 Aug 6.
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.
BH3 仅结构域促凋亡蛋白 BIK 受泛素蛋白酶体系统调控。然而，这种调控的机制及其生理功能仍不清楚。在这里，我们鉴定出 Cul5-ASB11 是一种 E3 连接酶，可将 BIK 作为泛素化和降解的靶标。内质网应激导致 XBP1s 在未折叠蛋白反应的适应性阶段激活 ASB11，从而刺激 BIK 泛素化、与 p97/VCP 的相互作用和蛋白水解。这种 BIK 降解机制通过促进细胞存活有助于内质网应激适应。相反，遗传毒性药物下调 IRE1α-XBP1s-ASB11 轴并稳定 BIK，这部分有助于 DNA 损伤的凋亡反应。我们表明，通过 IRE1α 抑制剂阻断这种 BIK 降解途径可以稳定 BIK 活性突变体并增加其抗肿瘤活性。我们的研究揭示了不同的细胞应激通过 ASB11 以相反的方向调节 BIK 的泛素化，这决定了细胞是否存活，并且阻断 BIK 降解有可能被用作抗癌策略。
