EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

Bearss, Jeremiah J.; Padi, Megha; Singh, Neha; Cardó-Vila, Marina; Song, Jin H.; Mouneimne, Ghassan; Fernandes, Nikita; Li, Yang; Harter, Matthew R.; Gard, Jaime M.C.; Cress, Anne E.; Peti, Wolfgang; Nelson, Andrew D. L.; Buchan, J. Ross; Kraft, Andrew S.; Okumura, Kōichi

doi:10.15252/embr.202050835

Cited by 24 publications

(24 citation statements)

References 88 publications

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“…Inspired by the paradigmatic demonstration that positively charged peptides can form liquid droplets in the presence of RNA in vitro , and that phosphorylation of specific amino acid residues within these peptides drives liquid phase remixing of peptide-RNA coacervates, we propose that post-translational modifications of NBDY could control phase separation of P-body components. Importantly, such a phenomenon has been previously shown for several P-body proteins whose phosphorylation promotes P-body dissociation. , In this work, we demonstrate that NBDY phase separates in the presence of RNA under specific conditions in vitro , and that phosphorylation of NBDY dissociates these liquid droplets. We further show that NBDY is a master regulator of P-bodies in cells, taking phosphorylation inputs from multiple signaling pathways to promote P-body disappearance prior to cell division.…”

Section: Introductionsupporting

confidence: 75%

Phosphorylation of a Human Microprotein Promotes Dissociation of Biomolecular Condensates

Luo

Cui

et al. 2021

J. Am. Chem. Soc.

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Proteogenomic identification of translated small open reading frames in humans has revealed thousands of microproteins, or polypeptides of fewer than 100 amino acids, that were previously invisible to geneticists. Hundreds of microproteins have been shown to be essential for cell growth and proliferation, and many regulate macromolecular complexes. However, the vast majority of microproteins remain functionally uncharacterized, and many lack secondary structure and exhibit limited evolutionary conservation. One such intrinsically disordered microprotein is NBDY, a 68-amino acid component of membraneless organelles known as P-bodies. In this work, we show that NBDY can undergo liquid−liquid phase separation, a biophysical process thought to underlie the formation of membraneless organelles, in the presence of RNA in vitro. Phosphorylation of NBDY drives liquid phase remixing in vitro and macroscopic P-body dissociation in cells undergoing growth factor signaling and cell division. These results suggest that NBDY phosphorylation enables regulation of P-body dynamics during cell proliferation and, more broadly, that intrinsically disordered microproteins may contribute to liquid−liquid phase separation and remixing behavior to affect cellular processes.

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Section: Introductionsupporting

confidence: 75%

Phosphorylation of a Human Microprotein Promotes Dissociation of Biomolecular Condensates

Luo

Cui

et al. 2021

J. Am. Chem. Soc.

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“…ATXN2 has been reported to be overexpressed in pancreatic adenocarcinoma (PAAD) tumor tissues, and overexpression of ATXN2 promotes PADD cell proliferation, migration, and invasion ( Fang et al, 2021 ). EDC3 plays an important role in regulating RNA decapping and destruction in cancer progression, and it can also promote tumor growth and invasion ( Bearss et al, 2021 ). However, the expression level and clinical value of LSM10, ATXN2 , and EDC3 in HCC have not been explored.…”

Section: Discussionmentioning

confidence: 99%

Determining the Prognostic Value of Spliceosome-Related Genes in Hepatocellular Carcinoma Patients

Lee

Zhang

et al. 2022

Front. Mol. Biosci.

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Background: The spliceosome plays an important role in mRNA alternative splicing and is aberrantly expressed in several tumors. However, the potential roles of spliceosome-related genes in the progression of hepatocellular carcinoma (HCC) remain poorly understood.Materials and Methods: Patient data were acquired from public databases. Expression differences and survival analyses were used to assess the importance of spliceosome-related genes in HCC prognosis. To explore the potential regulatory mechanisms of these genes, a protein-protein interaction network was constructed and screened using univariate and multivariate Cox regression and random forest analyses. This was used to create a five-gene prognostic model. The prognostic value and predictive power of the five-gene signature were assessed using the Kaplan-Meier and time-dependent receiver operating characteristic analyses in the training set. These results were further validated in an independent external set. To facilitate clinical application, a nomogram was prepared to predict the overall survival of HCC patients. The relative expression of five genes was detected using real-time quantitative polymerase chain reaction.Results: The analysis revealed that LSM1-7, SNRPB, SNRPD1-3, SNRPE, SNRPF, SNRPG, and SNRPN could be used as prognostic biomarkers in HCC patients. Moreover, the five-gene risk model could clearly distinguish between the high-and low-risk groups. Furthermore, the risk model was associated with the tumor mutation burden, immune cell infiltration of CD8+ T cells, natural killer T cells, M2 macrophages, and immune checkpoint inhibitors, which also demonstrated the predictive efficacy of this risk model in HCC immunotherapy.Conclusion: Spliceosome-related genes and the five-gene signature could serve as novel prognostic biomarkers for HCC patients, aiding clinical patient monitoring and follow-up.

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“…A few examples have recently emerged. For example, phosphorylation of Edc3 and Edc4 by the Pim1/3 kinase and the IκB kinase (IKK), respectively, promote their localization to P bodies in human cells ( Mikuda et al, 2018 ; Bearss et al, 2021 ). Similarly, ubiquitination and phosphorylation of Dcp1 by the TRAF6-JNK signaling pathway upon cytokine induction is important for Dcp1 to localize to P bodies ( Tenekeci et al, 2016 ).…”

Section: Perspective and Emerging Questionsmentioning

confidence: 99%

Eukaryotic mRNA Decapping Activation

Vidya

2022

Front. Genet.

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The 5′-terminal cap is a fundamental determinant of eukaryotic gene expression which facilitates cap-dependent translation and protects mRNAs from exonucleolytic degradation. Enzyme-directed hydrolysis of the cap (decapping) decisively affects mRNA expression and turnover, and is a heavily regulated event. Following the identification of the decapping holoenzyme (Dcp1/2) over two decades ago, numerous studies revealed the complexity of decapping regulation across species and cell types. A conserved set of Dcp1/2-associated proteins, implicated in decapping activation and molecular scaffolding, were identified through genetic and molecular interaction studies, and yet their exact mechanisms of action are only emerging. In this review, we discuss the prevailing models on the roles and assembly of decapping co-factors, with considerations of conservation across species and comparison across physiological contexts. We next discuss the functional convergences of decapping machineries with other RNA-protein complexes in cytoplasmic P bodies and compare current views on their impact on mRNA stability and translation. Lastly, we review the current models of decapping activation and highlight important gaps in our current understanding.

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EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

Cited by 24 publications

References 88 publications

Phosphorylation of a Human Microprotein Promotes Dissociation of Biomolecular Condensates

Phosphorylation of a Human Microprotein Promotes Dissociation of Biomolecular Condensates

Determining the Prognostic Value of Spliceosome-Related Genes in Hepatocellular Carcinoma Patients

Eukaryotic mRNA Decapping Activation

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