E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma.
E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma.
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作者：
Li Y;Bao L;Zheng H;Geng M;Chen T;Dai X;Xiao H;Yang L;Mao C;Qiu Y;Xu Y;Wang D;Li MX;Chen Q
背景：对泛素化机制的阐明为胶质母细胞瘤（GBM）的治疗带来了新的途径。TRIM蛋白介导的可逆的、严格的泛素化与胶质瘤的恶性程度密切相关。本研究旨在筛选三肽基序蛋白中最重要、最异常的调控组分，并探讨其作用机制。研究方法：TRIM 21被鉴定为一种重要的癌基因，其以多维方式通过数据库加速神经胶质瘤细胞的进展，并且这在人类样品和细胞中得到证实。通过串联质谱（TMT）和质谱（MS）分析发现TRIM 21的底物，并通过CO-IP、荧光素酶报告基因分析和功能获得和丧失分析进一步研究其作用机制。应用siRNA的体内治疗来评估TRIM 21的治疗意义。测试结果：我们筛选了一组TRIM蛋白，并鉴定了TRIM 21，一种E3泛素蛋白连接酶和自身抗原，以及GBM的预后生物标志物。在功能上，野生型TRIM 21的高表达在体外和体内加速肿瘤进展，而TRIM 21突变体，包括具有关键环指缺失的突变体，则不会。从机制上讲，TRIM 21刺激K63连接的泛素化和活性β-连环蛋白从细胞质到细胞核的亚细胞易位。此外，TRIM 21在细胞核中与β-连环蛋白上游调节因子TIF 1 γ形成复合物，并通过诱导K5位点处的K48连接的泛素化来加速其降解，从而进一步增加细胞核中β-连环蛋白的存在。在胶质瘤组织微阵列实验中发现内源性TRIM 21水平与TIF 1 γ负相关，但与β-连环蛋白正相关。此外，TRIM 21小干扰RNA（siRNA）直接注射到U87细胞来源的肿瘤中（用siRNA体内处理）被证明抑制裸鼠中的肿瘤生长。结论：TRIM 21/TIF 1 γ/β-catenin轴参与了人GBM的发生发展。TRIM 21是一个有前途的β-catenin高活性胶质瘤治疗和预后的生物标志物。
Background: Elucidation of the mechanism of ubiquitation has led to novel ways to treat glioblastoma (GBM). A tripartite motif (TRIM) protein mediates a reversible, stringent ubiquitation which is closely related to glioma malignancy. This study intends to screen the most vital and abnormal regulating component of the tripartite motif protein and to explore its underlying mechanisms. Methods: TRIM21 is identified as an important oncogene that accelerates the progression of glioma cell through database in a multidimensional way and this is confirmed in human samples and cells. Tandem Mass Tags (TMT) and MS analysis are performed to discover the substrates of TRIM21.The underlying mechanisms are further investigated by CO-IP, luciferase reporter assays and gain and loss of function assays. In vivo treatment with siRNA is applied to evaluate the therapeutic significance of TRIM21. Result: We screened a panel of TRIM proteins and identified TRIM21, a E3 ubiquitin-protein ligase and autoantigen, as well as a prognostic biomarker for GBM. Functionally, high expression of wild-type TRIM21 accelerates tumor progression in vitro and in vivo, whereas TRIM21 mutants, including one with a critical RING-finger deletion, do not. Mechanistically, TRIM21 stimulates K63-linked ubiquitination and subcellular translocation of active β-catenin from the cytoplasm to the nucleus. Moreover, TRIM21 forms a complex with the β-catenin upstream regulator, TIF1γ, in the nucleus and accelerated its degradation by inducing K48-linked ubiquitination at K5 site, consequently increasing further nuclear β-catenin presence. Endogenous TRIM21 levels are found to be inversely correlated with TIF1γ but positively correlated with β-catenin in glioma tissue microarray experiments. Furthermore, direct injection of TRIM21 small interfering RNA (siRNA) into U87 cell-derived tumors (in vivo treatment with siRNA) is proved to inhibit tumor growth in nude mice. Conclusion: This work suggests that TRIM21/TIF1γ/β-catenin axis is involved in the progression of human GBM. TRIM21 is a promising therapeutic and prognostic biomarker for glioma with hyperactive β-catenin.
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