C646 degrades Exportin-1 to modulate p300 chromatin occupancy and function

IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

Abstract

Molecular glues can induce proximity between a target protein and ubiquitin ligases to induce target degradation, but strategies for their discovery remain limited. We screened 3,200 bioactive small molecules and identified that C646 requires neddylation-dependent protein degradation to induce cytotoxicity. Although the histone acetyltransferase p300 is the canonical target of C646, we provide extensive evidence that C646 directly targets and degrades Exportin-1 (XPO1). Multiple cellular phenotypes induced by C646 were abrogated in cells expressing the known XPO1C528S drug-resistance allele. While XPO1 catalyzes nuclear-to-cytoplasmic transport of many cargo proteins, it also directly binds chromatin. We demonstrate that p300 and XPO1 co-occupy hundreds of chromatin loci. Degrading XPO1 using C646 or the known XPO1 modulator S109 diminishes the chromatin occupancy of both XPO1 and p300, enabling direct targeting of XPO1 to phenocopy p300 inhibition. This work highlights the utility of drug-resistant alleles and further validates XPO1 as a targetable regulator of chromatin state.

Abstract Image

Abstract Image

C646 降解 Exportin-1,从而调节 p300 染色质占有率和功能
分子粘合剂可诱导靶蛋白与泛素连接酶之间的接近,从而诱导靶蛋白降解,但发现这种粘合剂的策略仍然有限。我们筛选了 3,200 种具有生物活性的小分子,发现 C646 需要依赖于内切酶的蛋白质降解来诱导细胞毒性。虽然组蛋白乙酰转移酶 p300 是 C646 的典型靶点,但我们提供了大量证据,证明 C646 直接靶向并降解 Exportin-1 (XPO1)。在表达已知 XPO1C528S 耐药等位基因的细胞中,C646 诱导的多种细胞表型均被削弱。XPO1 催化了许多货物蛋白从细胞核到细胞质的转运,它还能直接结合染色质。我们证明 p300 和 XPO1 共同占据了数百个染色质位点。使用 C646 或已知的 XPO1 调制剂 S109 降解 XPO1 会减少 XPO1 和 p300 的染色质占有率,从而实现直接靶向 XPO1 以表征 p300 抑制。这项工作强调了耐药等位基因的作用,并进一步验证了 XPO1 是染色质状态的靶向调节因子。
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来源期刊
Cell Chemical Biology
Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍: Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.
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