PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1

Gao, Guozhen; Dhar, Surbhi; Bedford, Mark T.

doi:10.1093/nar/gkw1367

Cited by 63 publications

(94 citation statements)

References 67 publications

(93 reference statements)

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“…We found that the two techniques were mostly orthogonal for both methyl peptide identification and LFQ quantitation, demonstrating that comprehensive measurement of the protein methylome requires multiple methyl peptide enrichment strategies. Although SCX and IAP enrich different methyl peptides, both SCX and IAP peptides were enriched for the GO annotation RNA binding, consistent with the known function of protein methylation (11,24,(43)(44)(45)(46)(47) (Fig. 1D).…”

Section: Discussionsupporting

confidence: 72%

“…Gene ontology analysis of methyl peptides identified by SCX and IAP demonstrated that both techniques were highly enriched for RNA binding proteins ( Fig. 1D), in agreement with known properties of methyl proteins (11,24,(43)(44)(45)(46)(47). In addition, IAP enriched proteins related to DNA binding and transcription factor binding, whereas SCX enriched proteins related to nucleoside-triphosphatase activity and hydrolase activity.…”

Section: Scx and Iap Enrich Methyl Peptides And Target Different Subssupporting

confidence: 74%

“…Taken together, this data indicates that HNRNPA1 R206 can exist as either ADMA and SDMA and suggests that PRMT1 knockdown results in a switch from ADMA to SDMA. This finding is particularly interesting because switching between methyl forms can affect protein function (12) and PRMT5-mediated methylation of HNRNPA1 regulates translation mRNAs containing internal ribosome entry sites (44). Thus, PRMT1 and the interplay between ADMA and SDMA modifications may regulate HNRNPA1 activity.…”

Section: Recent Reports Have Indicated That the Neutral Losses Of Dimmentioning

confidence: 98%

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Deep protein methylation profiling by combined chemical and immunoaffinity approaches reveals novel PRMT1 targets

Hartel

Chew

Qin

et al. 2019

Preprint

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Running title: Deep methylation profiling reveals novel PRMT1 targetsDeep methylation profiling reveals novel PRMT1 targets 2 ABBREVIATIONS ADMA, asymmetric dimethyl arginine; DMA, dimethyl arginine; HILIC, hydrophilic interaction chromatography; IAP, immunoaffinity purification; Kme1, monomethyl lysine; Kme2, dimethyl lysine; Kme3, trimethyl lysine; KMT, lysine methyltransferase; LC, liquid chromatography; LFQ, label-free quantitation; MS, mass spectrometry; MMA, monomethyl arginine; PTM, posttranslational modification; PRMT, protein arginine methyltransferase; SCX, strong cation exchange; SDMA, symmetric dimethyl arginine;Deep methylation profiling reveals novel PRMT1 targets 3 ABSTRACT Protein methylation has been implicated in many important biological contexts including signaling, metabolism, and transcriptional control. Despite the importance of this post-translational modification, the global analysis of protein methylation by mass spectrometry-based proteomics has not been extensively studied due to the lack of robust, well-characterized techniques for methyl peptide enrichment. Here, to better investigate protein methylation, we compared two methods for methyl peptide enrichment: immunoaffinity purification (IAP) and high pH strong cation exchange (SCX). Using both methods, we identified 1,720 methylation sites on 778 proteins. Comparison of these methods revealed that they are largely orthogonal, suggesting that the usage of both techniques is required to provide a global view of protein methylation. Using both IAP and SCX, we then investigated changes in protein methylation downstream of protein arginine methyltransferase 1 (PRMT1). PRMT1 knockdown resulted in significant changes to 127 arginine methylation sites on 78 proteins. In contrast, only a single lysine methylation site was significantly changed upon PRMT1 knockdown. In PRMT1 knockdown cells, we found 114 MMA sites that were either significantly downregulated or upregulated on proteins enriched for mRNA metabolic processes. PRMT1 knockdown also induced significant changes in both asymmetric dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA). Using characteristic neutral loss fragmentation ions, we annotated dimethylarginines as either ADMA or SDMA. Through integrative analysis of methyl forms, we identified 18 high confidence PRMT1 substrates and 12 methylation sites that are scavenged by other non-PRMT1 arginine methyltransferases in the absence of PRMT1 activity. We also identified one methylation site, HNRNPA1 R206, which switched from ADMA to SDMA upon PRMT1 knockdown. Taken together, our results suggest that deep protein methylation profiling by mass spectrometry requires orthogonal enrichment techniques to identify novel PRMT1 methylation targets and highlight the dynamic interplay between methyltransferases in mammalian cells. Deep methylation profiling reveals novel PRMT1 targets

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Section: Discussionsupporting

confidence: 72%

Section: Scx and Iap Enrich Methyl Peptides And Target Different Subssupporting

confidence: 74%

Section: Recent Reports Have Indicated That the Neutral Losses Of Dimmentioning

confidence: 98%

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Deep protein methylation profiling by combined chemical and immunoaffinity approaches reveals novel PRMT1 targets

Hartel

Chew

Qin

et al. 2019

Preprint

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“…In turn, RIOK1—as part of the PRMT5 complex—promotes the translation of c-Myc transcripts (26). Hence, it is not surprising that RIOK1 is overexpressed in myriad malignancies (145).…”

Section: Discussionmentioning

confidence: 99%

Integrating Rio1 activities discloses its nutrient-activated network in Saccharomyces cerevisiae

Iacovella

Bremang

Basha

et al. 2018

Nucleic Acids Research

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The Saccharomyces cerevisiae kinase/adenosine triphosphatase Rio1 regulates rDNA transcription and segregation, pre-rRNA processing and small ribosomal subunit maturation. Other roles are unknown. When overexpressed, human ortholog RIOK1 drives tumor growth and metastasis. Likewise, RIOK1 promotes 40S ribosomal subunit biogenesis and has not been characterized globally. We show that Rio1 manages directly and via a series of regulators, an essential signaling network at the protein, chromatin and RNA levels. Rio1 orchestrates growth and division depending on resource availability, in parallel to the nutrient-activated Tor1 kinase. To define the Rio1 network, we identified its physical interactors, profiled its target genes/transcripts, mapped its chromatin-binding sites and integrated our data with yeast’s protein–protein and protein–DNA interaction catalogs using network computation. We experimentally confirmed network components and localized Rio1 also to mitochondria and vacuoles. Via its network, Rio1 commands protein synthesis (ribosomal gene expression, assembly and activity) and turnover (26S proteasome expression), and impinges on metabolic, energy-production and cell-cycle programs. We find that Rio1 activity is conserved to humans and propose that pathological RIOK1 may fuel promiscuous transcription, ribosome production, chromosomal instability, unrestrained metabolism and proliferation; established contributors to cancer. Our study will advance the understanding of numerous processes, here revealed to depend on Rio1 activity.

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“…Although arginine methylation has been mostly associated with changes in protein-protein interactions (50,51), there are previous examples of direct modulation of RNA-protein binding in mammalian cells (52)(53)(54). PRMTs have previously been shown to regulate the RNA affinity of target RBPs in other systems (55,56).…”

Section: Discussionmentioning

confidence: 99%

Post-translational epigenetics: PRMT7 regulates RNA-binding capacity and protein stability to controlLeishmaniaparasite virulence

Ferreira

Dowle

Parry

et al. 2019

Preprint

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RNA binding proteins (RBPs) are the primary gene regulators in kinetoplastids as transcriptional control is nearly absent, making Leishmania an exceptional model for investigating methylation of non-histone substrates. Arginine methylation is an evolutionarily conserved protein modification catalyzed by Protein aRginine MethylTransferases (PRMTs). The chromatin modifier PRMT7 is the only Type III PRMT found in higher eukaryotes and a restricted number of unicellular eukaryotes.In Leishmania major, PRMT7 is a cytoplasmic protein implicit in pathogenesis with unknown substrates. Using comparative methyl-SILAC proteomics for the first time in protozoa, we identified 40 putative targets, including 17 RBPs hypomethylated upon PRMT7 knockout. PRMT7can modify Alba3 and RBP16 trans-regulators (mammalian RPP25 and YBX2 homologs, respectively) as direct substrates in vitro. The absence of PRMT7 levels in vivo selectively reduces Alba3 mRNA-binding capacity to specific target transcripts and can impact the relative stability of RBP16 in the cytoplasm. RNA immunoprecipitation analyses demonstrate PRMT7-dependent methylation promotes Alba3 association with select target transcripts and stability of δ-amastin surface antigen. These results highlight a novel role for PRMT7-mediated arginine methylation upon RBP substrates, suggesting a regulatory pathway controlling gene expression and virulence in Leishmania. This work introduces Leishmania PRMTs as epigenetic regulators of mRNA metabolism with mechanistic insight into the functional manipulation of RBPs by methylation.

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PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1

Cited by 63 publications

References 67 publications

Deep protein methylation profiling by combined chemical and immunoaffinity approaches reveals novel PRMT1 targets

Deep protein methylation profiling by combined chemical and immunoaffinity approaches reveals novel PRMT1 targets

Integrating Rio1 activities discloses its nutrient-activated network in Saccharomyces cerevisiae

Post-translational epigenetics: PRMT7 regulates RNA-binding capacity and protein stability to controlLeishmaniaparasite virulence

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