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PRMT5-mediated intron retention triggers innate and adaptive immunity against cancer

ABSTRACT: PRMT5 is expressed at high levels in many cancers, where it regulates diverse cellular pathways that contribute to oncogenesis. Here, we have defined a new role for PRMT5 in regulating and coordinating the interplay between the innate and adaptive immune response. This occurs through the influence of PRMT5 on RNA splicing and the presence of retained introns (RIs). We found that RIs, which occur upon PRMT5 inhibition, have a propensity to form double-stranded RNA structures which activate the innate immune response. Furthermore, many RIs contain cryptic open reading frames which can be translated and then processed into small peptides that assemble with the MHC class I complex. Significantly, RI-derived peptides are highly immunogenic and a murine cancer vaccine, carrying a string of antigenic RI peptides, delayed tumour growth and enhanced survival. RIs are present in human tumour cells, and we identified T lymphocytes in cancer patients with antigen specificity for RI-derived peptides that killed human tumour cells in vitro. Regulating intron retention thus offers a new therapeutic approach to regulate tumour immunogenicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327671 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description: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 survival and early stages of differentiation. However, besides its nuclear localization, PRMT5 is found at high levels in the cytoplasm of oligodendrocyte progenitor cells (OPCs) and yet, its interacting partners and non-histone substrates in this lineage, remain elusive. By using mass spectrometry on protein eluates from extracts generated from OPC and immunoprecipitated with PRMT5 antibodies, we identified 1116 proteins as PRMT5 interacting partners. These proteins are related to molecular functions such as RNA binding, ribosomal structure, nucleotide binding, cadherin and actin binding, GTP and GTPase activity. We then investigated PRMT5 substrates using iTRAQ-based proteomics on protein samples isolated from CRISPR-PRMT5 knockdown immortalized oligodendrocyte progenitors compared to CRISPR-EGFP controls. This analysis identified 169 peptides with statistically different symmetric methylation of arginine residues in the two groups. Those peptides led to 30 unique non-histone substrates of PRMT5. The majority of these proteins were consistent with PRMT5 substrates, previously identified in distinct cancer cell lines (e.g. the transcription factor ZN326), and were functionally related to RNA processing and transport, splicing, regulation of mRNA stability and transcription. In addition, we detected three substrates as unique to the oligodendrocyte lineage and not identified in cancer cells. They included the proline-rich protein PRC2C, involved in methyl-RNA binding, the RNA binding protein KHDR2, regulating splicing events and the heterogeneous nuclear RNA binding protein HNRPD, involved in regulation of RNA stability. Together, these results highlight a cell-specific role of PRMT5 in regulating, not only transcription, but RNA processing and translation in OPCs. (287 WORDS)

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PRMT5-mediated intron retention triggers innate and adaptive immunity against cancer

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