核积累和杀抑制剂BIRC2的向的分子基础
Adam H Tencer1, Yucong Yu2, Sebastien Z Causse3
1Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
Nature structural & molecular biology
|July 31, 2023
概括
亡蛋白抑制剂BIRC2与细胞核中的组素H3结合,影响细胞死亡和DNA修复. 一种小分子抑制剂LCL161破坏了这种相互作用,促进癌细胞死亡,并在感染HIV的细胞中降解BIRC2.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 亡蛋白抑制剂BIRC2 (也称为cIAP1) 是细胞死亡和生存途径的关键调节者.
- BIRC2的核积累会影响基本的细胞过程,但其机制尚不清楚.
研究的目的:
- 阐明BIRC2核积累的机制及其功能后果.
- 描述BIRC2与素H3结合的结构基础.
- 调查针对治疗干预的小分子抑制剂针对BIRC2的潜力.
主要方法:
- 共同免疫沉和西部涂抹以研究BIRC2 - 希斯H3相互作用.
- 进行X射线晶体学以确定BIRC2BIR3-H3复合物的结构.
- RNA测序 (RNA-seq) 用于分析BIRC2枯竭后的基因表达变化.
- 细胞活力测定和DNA损伤反应评估.
- 生物化学试验以表征小分子抑制剂LCL161.1.
主要成果:
- BIRC2通过将其BIR2和BIR3域与基因素H3尾部结合而积聚在细胞核中.
- BIRC2BIR3-H3复合物的晶体结构揭示了这种相互作用的分子细节.
- BIRC2 枯竭显著影响参与干扰素/防御反应和细胞周期调节的基因.
- 过度表达BIRC2会影响DNA损伤的修复和细胞周期的恢复.
- 小分子抑制剂LCL161在结构上准BIRC2,破坏BIRC2-H3的结合,并诱导癌细胞死亡.
- 此外,LCL161还调解了HIV-1感染的CD4+ T细胞中的BIRC2降解.
结论:
- BIRC2的核定位是通过直接结合基因素H3来调节的,这会影响基因表达和DNA修复.
- 通过破坏BIRC2-H3相互作用,导致癌细胞死亡并影响病毒与宿主相互作用,LCL161代表了一个有前途的治疗剂.
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