Type I arginine methyltransferases are intervention points to unveil the oncogenic Epstein-Barr virus to the immune system

Angrand, Gaelle; Quillévéré, Alicia; Dinh, Van-Trang; Sénéchal, Ronan Le; Chennoufi, Rahima; Duchambon, Patricia; Keruzoré, Marc; Martins, Rodrigo Prado; Teulade‐Fichou, Marie‐Paule; Fåhræus, Robin; Blondel, Marc

doi:10.1093/nar/gkac915

Cited by 7 publications

(5 citation statements)

References 65 publications

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“…Phenylalanine is frequently distributed in the GAR domains of FNG in the GFRG or GFG context. Due to the hydrophobicity and π electrons, phenylalanine has been used as a methylarginine mimic in some studies [27][28][29][30][31]. It is possible that in the extra-long GAR domains of the nucleolar proteins, F might function like a constitutive methylarginine in the context.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Glycine- and Arginine-Rich Motifs in Proteins by a Novel GAR Motif Finder Program

Wang

Huang

Chang

et al. 2023

Genes

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Glycine- and arginine-rich (GAR) motifs with different combinations of RG/RGG repeats are present in many proteins. The nucleolar rRNA 2′-O-methyltransferase fibrillarin (FBL) contains a conserved long N-terminal GAR domain with more than 10 RGG plus RG repeats separated by specific amino acids, mostly phenylanalines. We developed a GAR motif finder (GMF) program based on the features of the GAR domain of FBL. The G(0,3)-X(0,1)-R-G(1,2)-X(0,5)-G(0,2)-X(0,1)-R-G(1,2) pattern allows the accommodation of extra-long GAR motifs with continuous RG/RGG interrupted by polyglycine or other amino acids. The program has a graphic interface and can easily output the results as .csv and .txt files. We used GMF to show the characteristics of the long GAR domains in FBL and two other nucleolar proteins, nucleolin and GAR1. GMF analyses can illustrate the similarities and also differences between the long GAR domains in the three nucleolar proteins and motifs in other typical RG/RGG-repeat-containing proteins, specifically the FET family members FUS, EWS, and TAF15 in position, motif length, RG/RGG number, and amino acid composition. We also used GMF to analyze the human proteome and focused on the ones with at least 10 RGG plus RG repeats. We showed the classification of the long GAR motifs and their putative correlation with protein/RNA interactions and liquid–liquid phase separation. The GMF algorithm can facilitate further systematic analyses of the GAR motifs in proteins and proteomes.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Glycine- and Arginine-Rich Motifs in Proteins by a Novel GAR Motif Finder Program

Wang

Huang

Chang

et al. 2023

Genes

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“…RNA pulldowns experiments were performed as previously described ( 27 , 31 ). Briefly, the following G-quadruplex forming RNA oligonucleotides 3′-tagged with tetraethylene glycol (TEG)-Biotin were used:…”

Section: Methodsmentioning

confidence: 99%

Alternative splicing of BCL-x is controlled by RBM25 binding to a G-quadruplex in BCL-x pre-mRNA

Le Sénéchal,

Keruzoré,

Quillévéré

et al. 2023

Nucleic Acids Research

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BCL-x is a master regulator of apoptosis whose pre-mRNA is alternatively spliced into either a long (canonical) anti-apoptotic Bcl-xL isoform, or a short (alternative) pro-apoptotic Bcl-xS isoform. The balance between these two antagonistic isoforms is tightly regulated and overexpression of Bcl-xL has been linked to resistance to chemotherapy in several cancers, whereas overexpression of Bcl-xS is associated to some forms of diabetes and cardiac disorders. The splicing factor RBM25 controls alternative splicing of BCL-x: its overexpression favours the production of Bcl-xS, whereas its downregulation has the opposite effect. Here we show that RBM25 directly and specifically binds to GQ-2, an RNA G-quadruplex (rG4) of BCL-x pre-mRNA that forms at the vicinity of the alternative 5′ splice site leading to the alternative Bcl-xS isoform. This RBM25/rG4 interaction is crucial for the production of Bcl-xS and depends on the RE (arginine-glutamate-rich) motif of RBM25, thus defining a new type of rG4-interacting domain. PhenDC3, a benchmark G4 ligand, enhances the binding of RBM25 to the GQ-2 rG4 of BCL-x pre-mRNA, thereby promoting the alternative pro-apoptotic Bcl-xS isoform and triggering apoptosis. Furthermore, the screening of a combinatorial library of 90 putative G4 ligands led to the identification of two original compounds, PhenDH8 and PhenDH9, superior to PhenDC3 in promoting the Bcl-xS isoform and apoptosis. Thus, favouring the interaction between RBM25 and the GQ-2 rG4 of BCL-x pre-mRNA represents a relevant intervention point to re-sensitize cancer cells to chemotherapy.

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“…In contrast, PRMT1 and PRMT3 methylate the host protein nucleolin (NCL) at the C-terminal RGG motif, which promotes the direct binding of NCL to the G-quadruplexes formed in EBNA1 mRNA. This NCL-mediated translational inhibition of EBNA1 ultimately results in the reduced production of EBNA1-derived antigenic peptides and immune evasion of EBV (Figure 6B) [131].…”

Section: Herpesviridaementioning

confidence: 99%

Protein arginine methylation in viral infection and antiviral immunity

Zheng,

Chen,

Ren

et al. 2023

Int. J. Biol. Sci.

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Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes including epigenetic gene regulation, genome stability maintenance, RNA metabolism, and stress-responsive signal transduction. The varying substrates and biological functions of arginine methylation in cancer and neurological diseases have been extensively discussed, providing a rationale for targeting PRMTs in clinical applications. An increasing number of studies have demonstrated an interplay between arginine methylation and viral infections. PRMTs have been found to methylate and regulate several host cell proteins and different functional types of viral proteins, such as viral capsids, mRNA exporters, transcription factors, and latency regulators. This modulation affects their activity, subcellular localization, protein-nucleic acid and protein-protein interactions, ultimately impacting their roles in various virus-associated processes. In this review, we discuss the classification, structure, and regulation of PRMTs and their pleiotropic biological functions through the methylation of histones and non-histones. Additionally, we summarize the broad spectrum of PRMT substrates and explore their intricate effects on various viral infection processes and antiviral innate immunity. Thus, comprehending the regulation of arginine methylation provides a critical foundation for understanding the pathogenesis of viral diseases and uncovering opportunities for antiviral therapy.

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Type I arginine methyltransferases are intervention points to unveil the oncogenic Epstein-Barr virus to the immune system

Cited by 7 publications

References 65 publications

Identification and Characterization of Glycine- and Arginine-Rich Motifs in Proteins by a Novel GAR Motif Finder Program

Identification and Characterization of Glycine- and Arginine-Rich Motifs in Proteins by a Novel GAR Motif Finder Program

Alternative splicing of BCL-x is controlled by RBM25 binding to a G-quadruplex in BCL-x pre-mRNA

Protein arginine methylation in viral infection and antiviral immunity

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