Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA.
Nat Struct Mol Biol. 2023 Sep;30(9):1265-1274. doi: 10.1038/s41594-023-01044-1. Epub 2023 Jul 31.
The inhibitor of apoptosis protein BIRC2 regulates fundamental cell death and survival signaling pathways. Here we show that BIRC2 accumulates in the nucleus via binding of its second and third BIR domains, BIRC2 and BIRC2, to the histone H3 tail and report the structure of the BIRC2-H3 complex. RNA-seq analysis reveals that the genes involved in interferon and defense response signaling and cell-cycle regulation are most affected by depletion of BIRC2. Overexpression of BIRC2 delays DNA damage repair and recovery of the cell-cycle progression. We describe the structural mechanism for targeting of BIRC2 by a potent but biochemically uncharacterized small molecule inhibitor LCL161 and demonstrate that LCL161 disrupts the association of endogenous BIRC2 with H3 and stimulates cell death in cancer cells. We further show that LCL161 mediates degradation of BIRC2 in human immunodeficiency virus type 1-infected human CD4 T cells. Our findings provide mechanistic insights into the nuclear accumulation of and blocking BIRC2.
凋亡抑制蛋白 BIRC2 调节基本的细胞死亡和存活信号通路。在这里，我们通过 BIRC2 的第二和第三 BIR 结构域与组蛋白 H3 尾部的结合，证明 BIRC2 可通过核积累，并报告 BIRC2-H3 复合物的结构。RNA-seq 分析显示，干扰素和防御反应信号以及细胞周期调控相关基因受 BIRC2 缺失的影响最大。BIRC2 的过表达会延迟 DNA 损伤修复和细胞周期进程的恢复。我们描述了一种强效但生化特性尚未确定的小分子抑制剂 LCL161 靶向 BIRC2 的结构机制，并证明 LCL161 破坏了内源性 BIRC2 与 H3 的结合，并刺激癌细胞死亡。我们进一步表明，LCL161 介导了人类免疫缺陷病毒 1 感染的人 CD4 T 细胞中 BIRC2 的降解。我们的研究结果为 BIRC2 的核积累和阻断提供了机制见解。
