IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Emanuela Senatore, Rosario Avolio, Laura Rinaldi, Francesco Chiuso, Maria A Oliva, Chiara D'Ambrosio, Antonio Giuseppe Bianco, Emiliano Dalla, Stefano Maria Pagnotta, Raffaella Flammia, Concetta Ambrosino, Domenico Memoli, Gabriele Turacchio, Sonia Ines Mimoune, Yves Toiron, Stephane Audebert, Luc Camoin, Luca Lignitto, Andrea Scaloni, Antonietta Arcella, Antonio Feliciello
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引用次数: 0

摘要

多形性胶质母细胞瘤(GBM)是最致命的成人恶性脑肿瘤。蛋白质合成失调导致癌细胞的可塑性,推动了多形性胶质母细胞瘤细胞的异质性、转移行为和耐药性。因此,了解支配蛋白质翻译的复杂网络和信号通路是治疗 GBM 的一个重要目标。在这里,我们发现了一个以 E3 泛素连接酶 praja2 为中心的新型信号网络,它控制着 GBM 中的蛋白质翻译。Praja2 与 RNA 螺旋酶 DDX6 形成多聚体复合物,后者可抑制加工体(P-bodies)内靶 RNA 的翻译。通过激活 G 蛋白偶联受体来刺激 cAMP 信号,可诱导 P-体通过 praja2 介导的 DDX6 非蛋白水解多泛素化组装。praja2基因失活会重塑DDX6/mRNA复合物和翻译多聚体,促进细胞衰老和GBM生长停滞。表达泛素化缺陷的DDX6突变体可抑制P-体的组装并维持GBM的生长。综上所述,我们的研究结果确定了一个控制 P 型体翻译和 GBM 生长的 cAMP 驱动网络。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Praja2 controls P-body assembly and translation in glioblastoma by non-proteolytic ubiquitylation of DDX6.

Glioblastoma multiforme (GBM) is the most lethal form of malignant brain tumor in adults. Dysregulation of protein synthesis contributes to cancer cell plasticity, driving GBM cell heterogeneity, metastatic behavior, and drug resistance. Understanding the complex network and signaling pathways governing protein translation, is therefore an important goal for GBM treatment. Here we identify a novel signaling network centered on the E3 ubiquitin ligase praja2 that controls protein translation in GBM. Praja2 forms a multimeric complex with the RNA helicase DDX6, which inhibits translation of target RNAs within processing bodies (P-bodies). Stimulation of cAMP signaling through activation of G-protein-coupled receptors induces P-body assembly through praja2-mediated non-proteolytic polyubiquitylation of DDX6. Genetic inactivation of praja2 reshapes DDX6/mRNA complexes and translating polysomes and promotes cellular senescence and GBM growth arrest. Expression of an ubiquitylation-defective DDX6 mutant suppresses the assembly of P-bodies and sustains GBM growth. Taken together, our findings identify a cAMP-driven network that controls translation in P-bodies and GBM growth.

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来源期刊
EMBO Reports
EMBO Reports 生物-生化与分子生物学
CiteScore
11.20
自引率
1.30%
发文量
267
审稿时长
1 months
期刊介绍: EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry. 
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