核泛素化允许Hippo-YAP信号参与肝脏发育和肿瘤发生

IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jinsong Wei, Zhifa Cao, Qing Li, Xiaoyu Li, Qingzhe Wang, Yiming Zhang, Run Zhang, Xingru Wu, Quanhui Dai, Xinyang Li, Zhaocai Zhou, Fenyong Sun, Shi Jiao, Bing Zhao
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引用次数: 0

摘要

Hippo-YAP信号对器官发育和肿瘤发生至关重要。VGLL4占据TEAD阻止YAP结合,是Hippo-YAP活性的主要转录抑制因子。在这里,我们发现核E3连接酶泛素蛋白连接酶E3组分n-识别蛋白5 (UBR5)在Lys61上多泛素化VGLL4,使其降解,从而允许Hippo-YAP信号传导小鼠肝胆系统和人类多种癌症的发展。在小鼠肝脏发育过程中,Ubr5和Vgll4在时空上表现出相互的表达模式。Ubr5缺失损害了胆管细胞的发育和肝细胞的重编程,这可以通过切除Vgll4来恢复Hippo-YAP来有效地挽救。我们还发现UBR5-VGLL4-YAP轴与人类泛癌的进展有关。在多种类型的患者源性肿瘤类器官中靶向核E3连接酶可抑制其扩张。我们将UBR5鉴定为VGLL4的真正E3连接酶,提供了核希波- yap调控的分子框架,并提示核泛素化是yap依赖性恶性肿瘤的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Nuclear ubiquitination permits Hippo–YAP signal for liver development and tumorigenesis

Nuclear ubiquitination permits Hippo–YAP signal for liver development and tumorigenesis

Hippo–YAP signaling is crucial to organ development and tumorigenesis. VGLL4, which occupies TEAD to prevent YAP binding, is the main transcriptional repressor of Hippo–YAP activity. Here we identified the nuclear E3 ligase ubiquitin protein ligase E3 component n-recognin 5 (UBR5) poly-ubiquitinated VGLL4 at Lys61 for its degradation, which permits Hippo–YAP signaling for the development of the liver biliary system in mice and multiple cancers in humans. In mouse liver development, Ubr5 and Vgll4 exhibited reciprocal expression patterns spatiotemporally. Ubr5 deletion impaired cholangiocyte development and hepatocyte reprogramming, which could be efficiently rescued by restoring Hippo–YAP through ablating Vgll4. We also found that the UBR5–VGLL4–YAP axis is associated with the progression of human pan-cancers. Targeting nuclear E3 ligases in multiple types of patient-derived tumor organoids suppressed their expansion. Our identification of UBR5 as the bona fide E3 ligase of VGLL4 offers a molecular framework of nuclear Hippo–YAP regulation and suggests nuclear ubiquitination as a potential therapeutic target for YAP-dependent malignancies.

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来源期刊
Nature chemical biology
Nature chemical biology 生物-生化与分子生物学
CiteScore
23.90
自引率
1.40%
发文量
238
审稿时长
12 months
期刊介绍: Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.
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