HERC4与USP16协同通过稳定RPS15增强蛋白翻译以促进肺腺癌生长
HERC4 synergizes with USP16 to promote lung adenocarcinoma growth by augmenting protein translation via stabilizing RPS15.
作者
作者单位
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University & Guangdong Provincial Key Laboratory of Protein Modification and Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China. liangwh1987@163.com.
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University & Guangdong Provincial Key Laboratory of Protein Modification and Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China. xinliangmao@gzhmu.edu.cn.
摘要
中文
HERC4是HERC家族中知名的泛素连接酶,在多种癌症中发挥作用,但其在肺癌中的作用尚不清楚。本研究发现,HERC4在肺腺癌(LUAD)中存在显著表达失调,并促进LUAD细胞生长。机制上,HERC4与翻译相关蛋白相互作用,以不依赖于E3连接酶活性的方式特异性稳定40S核糖体亚基组分RPS15,促进其去泛素化。HERC4与去泛 ubiquit素酶USP16(同样与翻译相关蛋白相互作用)协同,通过阻止RPS15的K48连接泛素化来稳定RPS15。进一步研究表明,HERC4与USP16之间的相互作用对调控RPS15及促进LUAD细胞增殖至关重要。敲低HERC4或USP16可阻止翻译相关蛋白招募至核糖体,增加其核内滞留并降低全局翻译效率。过表达RPS15可部分恢复由HERC4/USP16敲低引起的翻译效率降低和细胞存活下降。此外,敲低HERC4或USP16通过RPS15失调上调p53并下调p38。总之,本研究揭示了一种对核糖体稳定性和蛋白翻译的新型泛素化调控机制。HERC4与USP16协同对RPS15进行去泛素化并稳定其表达,从而增强全局蛋白翻译,促进LUAD生长。HERC4/USP16-RPS15轴可能成为LUAD治疗的潜在靶点。
English
HERC4 is a well-known HERC family ubiquitin ligase in several types of cancer but its role in lung cancer remains elusive. In the present study, we found that HERC4 is highly dysregulated in lung adenocarcinoma (LUAD) and promotes LUAD cell growth. Mechanically, HERC4 interacts with translation-related proteins and specifically stabilizes RPS15, a component of 40S ribosomal subunit, by promoting its deubiquitination in a manner independent of E3 ligase activity. HERC4 collaborates with USP16, a deubiquitinase that also interacts with translation-related proteins, to stabilize RPS15 by preventing its K48-linked ubiquitination. Further studies revealed that the interaction between HERC4 and USP16 is important to regulate RPS15 and to promote LUAD cell proliferation. Knockdown of HERC4 or USP16 prevents the recruitment of translation-related proteins to ribosomes, increases their nuclear retention and reduces global translational efficacy. Overexpression of RPS15 partially rescues reduced protein translation efficiency and cell survival triggered by HERC4/USP16 knockdown. Moreover, knockdown of HERC4 or USP16 upregulates p53 and downregulates p38 via RPS15 dysregulation. In conclusion, the present study reveals a novel ubiquitination modulation on ribosomal stability and protein translation. HERC4 synergizes with USP16 to deubiquitinate and stabilize RPS15, thereby potentiating global protein translation and promoting LUAD growth. The HERC4/USP16-RPS15 axis may represent a potential therapeutic target for LUAD treatment.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 9.1
- 新锐分区
- 1区