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.
Authors
- Yves Toiron
- Stéphane Audebert (ORCID: https://orcid.org/0000-0002-9409-2588)
- Luca Lignitto (ORCID: https://orcid.org/0000-0001-6164-1299)
- Laura Rinaldi (ORCID: https://orcid.org/0000-0002-0975-2052)
- Luc Camoin (ORCID: https://orcid.org/0000-0002-1230-4787)
- Chiara DˈAmbrosio (ORCID: https://orcid.org/0000-0003-2810-9270)
- Domenico Memoli (ORCID: https://orcid.org/0000-0001-5290-2709)
- Concetta Ambrosino (ORCID: https://orcid.org/0000-0003-3954-8842)
- A BIANCO
- Rosario Avolio (ORCID: https://orcid.org/0000-0001-9573-1110)
- Maria Antonietta Oliva (ORCID: https://orcid.org/0000-0003-3460-696X)
- Antonio Feliciello (ORCID: https://orcid.org/0000-0002-7932-2170)
- Francesco Chiuso
- Antonietta Arcella (ORCID: https://orcid.org/0000-0002-0708-8282)
- Emanuela Senatore
- Raffaella Flammia
- Andrea Scaloni (ORCID: https://orcid.org/0000-0001-9362-8515)
- Stefano Maria Pagnotta (ORCID: https://orcid.org/0000-0002-8298-9777)
- Emiliano Dalla (ORCID: https://orcid.org/0000-0002-4687-6011)
- Gabriele Turacchio (ORCID: https://orcid.org/0000-0002-0959-3266)
- Sonia Ines Mimoune
Institutions
- University of Udine (IT)
- Centre National de la Recherche Scientifique (FR)
- University of Salerno (IT)
- Inserm (FR)
- University of Sannio (IT)
- Aix-Marseille Université (FR)
- Istituto Neurologico Mediterraneo (IT)
- Istituto per il Sistema Produzione Animale in Ambiente Mediterraneo (IT)
- Federico II University Hospital (IT)
- Centre de Recherche en Cancérologie de Marseille (FR)
- National Research Council (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1038/s44319-025-00425-5
- Citations
- 3
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Infrastructures en Biologie Santé et Agronomie
- Associazione Italiana per la Ricerca sul Cancro
- Canceropôle PACA
- Conseil Régional Provence-Alpes-Côte d'Azur
- Ministero dell'Università e della Ricerca
- European Regional Development Fund