Molecular basis for substrate recruitment to the PRMT5 methylosome

Mulvaney, Kathleen M.; Blomquist, Christa; Acharya, Nischal; Li, Ruitong; Ranaghan, Matthew J.; O’Keefe, Meghan; Rodriguez, Diego J.; Young, M. J. L.; Kesar, Devishi; Pal, Debjani; Stokes, Matthew P.; Nelson, Alissa J.; Jain, Sidharth; Yang, Annan; Mullin-Bernstein, Zachary; Columbus, Josie; Bozal, Fazli K.; Skepner, Adam; Raymond, D.D.; LaRussa, Salvatore; McKinney, David C.; Freyzon, Yelena; Baidi, Yossef; Porter, Dale; Aguirre, Andrew J.; Ianari, Alessandra; McMillan, Brian J.; Sellers, William R.

doi:10.1016/j.molcel.2021.07.019

Cited by 48 publications

(84 citation statements)

References 68 publications

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“…In common with many cell lines ( Musiani et al, 2019 ; Radzisheuskaya et al, 2019 ; Li et al, 2021 ; Mulvaney et al, 2021 ), we detected the majority of PRMT5 substrates involved in RNA splicing and processing. Among the common PRMT5 substrates ( Musiani et al, 2019 ; Radzisheuskaya et al, 2019 ; Li et al, 2021 ; Mulvaney et al, 2021 ), we identified: ROA1, a protein regulating translation at the internal ribosomal entry site ( Gao et al, 2017 ), the ribosomal protein RS10, whose arginine methylation is essential for proper ribosome assembly, and the zinc-finger protein ZN326, enriched in the oligodendrocyte lineage ( Zhang et al, 2014 ; Sharma et al, 2015 ) and regulated throughout development, with the highest expression in neuronal tissues in E11.5 embryos ( Lee et al, 2000 ). ZN326 complexes with nuclear messenger ribonucleoproteins (mRNPs) and Deleted in Breast Cancer 1 (DBC1) to form the regulatory DBIRD complex.…”

Section: Discussionmentioning

confidence: 59%

“…We then compared the PRMT5 substrates identified by our study in oligodendrocyte lineage cells to those previously reported in distinct tumors and cell lines ( Supplementary Table 6 ). Of the 57 substrates, 18 proteins (31.6%) were in common with the substrates previously identified in HeLa cells ( Musiani et al, 2019 ), 23 proteins (40.3%) were in common with those identified in human AML cells (human acute myeloid leukemia) ( Radzisheuskaya et al, 2019 ), 18 proteins (31.6%) in common with HEK293T cells ( Li et al, 2021 ), and 39 proteins (68.4%) with the MiaPaca2 cells (human pancreatic cancer cell line) ( Mulvaney et al, 2021 ; Figure 4B ). Among the proteins shared between oligodendrocyte progenitors and the cell lines, we identified the zinc-finger protein ZN326, the RNA binding protein involved in mRNA transport ROA1, and the spliceosome component RSMB, suggesting a common role of PRMT5 in related processes in distinct cell types ( Supplementary Table 6 ).…”

Section: Resultsmentioning

confidence: 79%

“… PRMT5 substrates in different cell lines. List of PRMT5 substrates identified in our study (immortalized oligodendrocyte progenitors), MiaPaca2 cells ( Mulvaney et al, 2021 ), HeLa cells ( Musiani et al, 2019 ), AML cells ( Radzisheuskaya et al, 2019 ), and HEK293 cells ( Li et al, 2021 ). Highlighted in red are substrates whose transcript levels are downregulated in PRMT5 KD cells ( Scaglione et al, 2018 ).…”

Section: Supplementary Materialsmentioning

confidence: 99%

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PRMT5 Interacting Partners and Substrates in Oligodendrocyte Lineage Cells

Dansu

Liang

Selcen

et al. 2022

Front. Cell. Neurosci.

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The protein arginine methyl transferase PRMT5 is an enzyme expressed in oligodendrocyte lineage cells and responsible for the symmetric methylation of arginine residues on histone tails. Previous work from our laboratory identified PRMT5 as critical for myelination, due to its transcriptional regulation of genes involved in survival and early stages of differentiation. However, besides its nuclear localization, PRMT5 is found at high levels in the cytoplasm of several cell types, including oligodendrocyte progenitor cells (OPCs) and yet, its interacting partners in this lineage, remain elusive. By using mass spectrometry on protein eluates from extracts generated from primary oligodendrocyte lineage cells and immunoprecipitated with PRMT5 antibodies, we identified 1196 proteins as PRMT5 interacting partners. These proteins were related to molecular functions such as RNA binding, ribosomal structure, cadherin and actin binding, nucleotide and protein binding, and GTP and GTPase activity. We then investigated PRMT5 substrates using iTRAQ-based proteomics on cytosolic and nuclear protein extracts from CRISPR-PRMT5 knockdown immortalized oligodendrocyte progenitors compared to CRISPR-EGFP controls. This analysis identified a similar number of peptides in the two subcellular fractions and a total number of 57 proteins with statistically decreased symmetric methylation of arginine residues in the CRISPR-PRMT5 knockdown compared to control. Several PRMT5 substrates were in common with cancer cell lines and related to RNA processing, splicing and transcription. In addition, we detected ten oligodendrocyte lineage specific substrates, corresponding to proteins with high expression levels in neural tissue. They included: PRC2C, a proline-rich protein involved in methyl-RNA binding, HNRPD an RNA binding protein involved in regulation of RNA stability, nuclear proteins involved in transcription and other proteins related to migration and actin cytoskeleton. Together, these results highlight a cell-specific role of PRMT5 in OPC in regulating several other cellular processes, besides RNA splicing and metabolism.

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Section: Discussionmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 79%

Section: Supplementary Materialsmentioning

confidence: 99%

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PRMT5 Interacting Partners and Substrates in Oligodendrocyte Lineage Cells

Dansu

Liang

Selcen

et al. 2022

Front. Cell. Neurosci.

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“… 47 Finally, another strategy has been to target the PRMT5 substrate adaptor interaction; BRD0639 disrupts the PRMT5-RIOK1 interactions required for the methylation of a variety of RIOK1-mediated, PRMT5-specific substrates. 48 The inhibitors referenced herein are listed in Table 1 (see below).…”

Section: Prmt5 In Inflammationmentioning

confidence: 99%

The Influence of Arginine Methylation in Immunity and Inflammation

Srour¹,

Khan²,

Richard³

2022

JIR

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Exploration in the field of epigenetics has revealed that protein arginine methyltransferases (PRMTs) contribute to disease, and this has given way to the development of specific small molecule compounds that inhibit arginine methylation. Protein arginine methylation is known to regulate fundamental cellular processes, such as transcription; pre-mRNA splicing and other RNA processing mechanisms; signal transduction, including the anti-viral response; and cellular metabolism. PRMTs are also implicated in the regulation of physiological processes, including embryonic development, myogenesis, and the immune system. Finally, the dysregulation of PRMTs is apparent in cancer, neurodegeneration, muscular disorders, and during inflammation. Herein, we review the functions of PRMTs in immunity and inflammation. We also discuss recent progress with PRMTs regarding the modulation of gene expression related to T and B lymphocyte differentiation, germinal center dynamics, and anti-viral signaling responses, as well as the clinical relevance of using PRMT inhibitors alone or in combination with other drugs to treat cancer, immune, and inflammatory-related diseases.

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“…Many proteins undergo modification in this manner, including transcription factors, various enzymes, and functional proteins, and also some spliceosome-associated proteins (Mckay and Johnson, 2010 ; Hu and Sun, 2016 ; Chanarat and Ishra, 2018 ; Xu, 2020 ). Indeed, PTMs of spliceosome components have recently emerged as major regulatory factors in yeast and human cells (Mckay and Johnson, 2010 ; Hu and Sun, 2016 ; Chanarat and Ishra, 2018 ; Pozzi et al, 2018 ; Xu, 2020 ; Li et al, 2021 ; Mulvaney et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitination and Ubiquitin-Like Modifications as Mediators of Alternative Pre-mRNA Splicing in Arabidopsis thaliana

Lan

Qiu

et al. 2022

Front. Plant Sci.

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Alternative splicing (AS) is a common post-transcriptional regulatory process in eukaryotes. AS has an irreplaceable role during plant development and in response to environmental stress as it evokes differential expression of downstream genes or splicing factors (e.g., serine/arginine-rich proteins). Numerous studies have reported that loss of AS capacity leads to defects in plant growth and development, and induction of stress-sensitive phenotypes. A role for post-translational modification (PTM) of AS components has emerged in recent years. These modifications are capable of regulating the activity, stability, localization, interaction, and folding of spliceosomal proteins in human cells and yeast, indicating that PTMs represent another layer of AS regulation. In this review, we summarize the recent reports concerning ubiquitin and ubiquitin-like modification of spliceosome components and analyze the relationship between spliceosome and the ubiquitin/26S proteasome pathway in plants. Based on the totality of the evidence presented, we further speculate on the roles of protein ubiquitination mediated AS in plant development and environmental response.

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Molecular basis for substrate recruitment to the PRMT5 methylosome

Cited by 48 publications

References 68 publications

PRMT5 Interacting Partners and Substrates in Oligodendrocyte Lineage Cells

PRMT5 Interacting Partners and Substrates in Oligodendrocyte Lineage Cells

The Influence of Arginine Methylation in Immunity and Inflammation

Ubiquitination and Ubiquitin-Like Modifications as Mediators of Alternative Pre-mRNA Splicing in Arabidopsis thaliana

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