Affinage

PRMT9

F-box only protein 11 · UniProt Q86XK2

Length
927 aa
Mass
103.6 kDa
Annotated
2026-06-10
17 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRMT9 is a type II protein arginine methyltransferase that deposits symmetric dimethylarginine (SDMA) on a defined set of substrates to control pre-mRNA splicing and several stress- and immune-signaling programs (PMID:25737013, PMID:38561334). Its catalytic activity depends on a C-terminal duplicated methyltransferase domain and unique double-E-loop residues, and unlike other PRMTs it requires full substrate protein context rather than recognizing isolated target peptides, giving it narrow, non-redundant specificity distinct from the principal SDMA enzyme PRMT5 (PMID:25979344). Its best-defined substrate is SF3B2 (SAP145), which PRMT9 methylates at Arg508 to create a Tudor-domain binding site for SMN, linking it to U2 snRNP maturation, and which it uses to control a methylation-sensitive SF3B2–pre-mRNA interaction governing splice-site selection; loss of PRMT9 produces genome-wide alternative splicing changes, with conditional knockout in hippocampal neurons causing aberrant synapse development and impaired learning, and the intellectual-disability G189R mutation abolishing activity and protein stability (PMID:25737013, PMID:38561334). Beyond splicing, PRMT9 methylates a distinct substrate panel to restrain signaling: it methylates MAVS at Arg41/Arg43 to suppress spontaneous aggregation and innate immune autoactivation at mitochondria (PMID:36028484), STAT1 at Arg588/Arg736 to drive its ubiquitination and selective autophagic degradation and limit M1 macrophage polarization (PMID:41669821), HSPA8 at Arg76/Arg100 to suppress ferroptosis via a CD44 axis (PMID:37715221), and DUSP26 at Arg29 to promote its Trim32-mediated proteasomal degradation with consequent mitochondrial dysfunction (PMID:42261762). In leukemia, PRMT9 sustains methylation of RNA-translation and DNA-damage-response regulators; its loss promotes DNA damage and cGAS-driven type I interferon signaling and re-sensitizes venetoclax-resistant AML through splicing and translational effects, making it a candidate therapeutic target (PMID:38413714, PMID:42118690, PMID:37560786).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2015 High

    Established PRMT9 as a bona fide type II arginine methyltransferase and identified its first physiological substrate, answering what reaction it catalyzes and on what target.

    Evidence In vitro methyltransferase assays, Co-IP, mass spectrometry and Arg508 mutagenesis identifying SF3B2 methylation and SMN Tudor-domain binding, with RNA-seq readout

    PMID:25737013

    Open questions at the time
    • Did not define structural basis of substrate selectivity
    • Splicing consequences characterized only by knockdown RNA-seq
  2. 2015 High

    Defined the catalytic architecture and substrate-recognition logic that distinguishes PRMT9 from other SDMA enzymes, explaining why it has narrow specificity.

    Evidence Site-directed mutagenesis of PRMT9 and SF3B2, in vitro assays with peptides versus full-length protein, and PRMT5-knockout MEFs

    PMID:25979344

    Open questions at the time
    • No high-resolution structure of the PRMT9–SF3B2 complex
    • Mechanism of full-protein-context recognition not resolved at atomic level
  3. 2006 Medium

    Provided an early demonstration of intrinsic arginine methyltransferase activity for a protein designated PRMT9, before substrate identity was known.

    Evidence Immunopurification from HeLa cells, recombinant E. coli expression and in vitro activity assays detecting MMA/SDMA/ADMA

    PMID:16487488

    Open questions at the time
    • No substrate identification or mutagenesis
    • ADMA formation not replicated by later PRMT9-focused work
    • Nomenclature overlap with FBXO11 complicates interpretation
  4. 2017 Medium

    Demonstrated evolutionary conservation of the PRMT9–SF3B2 axis, supporting it as the core ancestral function.

    Evidence In vitro methyltransferase assays with C. elegans PRMT-9 on recombinant SFTB-2

    PMID:28441492

    Open questions at the time
    • Conservation shown only biochemically, not in an organismal phenotype here
    • No comparison of additional substrates across species
  5. 2022 High

    Extended PRMT9 function beyond splicing by showing it gates innate antiviral signaling through methylation of a mitochondrial adaptor.

    Evidence Co-IP, in vitro methylation, R41/R43 mutagenesis, mitochondrial fractionation/imaging and MAVS aggregation assays

    PMID:36028484

    Open questions at the time
    • Trigger controlling PRMT9 dissociation from mitochondria not defined
    • Relationship between mitochondrial pool and nuclear splicing role unclear
  6. 2023 Medium

    Placed PRMT9 in a ferroptosis-suppressive pathway in hepatocellular carcinoma via methylation of a chaperone substrate.

    Evidence Co-IP, R76/R100 site-specific methylation, overexpression/knockdown with CD44 epistasis and in vivo tumor models

    PMID:37715221

    Open questions at the time
    • Mechanism linking HSPA8 methylation to CD44 upregulation not resolved
    • Single-lab finding without reciprocal validation
  7. 2024 High

    Established SF3B2 R508 methylation as the primary in vivo function of PRMT9 and connected it causally to splicing, neurodevelopment and intellectual disability.

    Evidence Conditional KO mice, SF3B2 methylation-deficient knock-in mice, G189R mutant, RNA-seq, electrophysiology, behavior and protein–RNA interaction assays

    PMID:38561334

    Open questions at the time
    • How splicing changes mechanistically produce synaptic defects not fully dissected
    • Contribution of non-SF3B2 substrates to the neuronal phenotype not quantified
  8. 2024 Medium

    Defined a therapeutic dependency in AML linking PRMT9 to RNA translation and DNA-damage-response methylation and to cGAS-driven immune activation.

    Evidence Genetic KO in AML lines and PDX, cGAS activation epistasis, type I IFN measurement and anti-PD1 combination in vivo

    PMID:38413714

    Open questions at the time
    • Direct methylated substrates among translation/DDR regulators not individually identified
    • Single-lab pathway placement
  9. 2026 High

    Showed PRMT9 restrains inflammatory macrophage polarization by routing a transcription factor to autophagic degradation, implicating it in cardiac injury.

    Evidence Co-IP/MS, R588/R736 methylation assays, autophagy-receptor interaction, macrophage-specific KO mice with myocardial infarction phenotype and AAV overexpression

    PMID:41669821

    Open questions at the time
    • Ubiquitin ligase coupling methylation to STAT1 degradation not identified
    • How methylation is read by autophagy receptors mechanistically unclear
  10. 2026 Medium

    Identified a substrate whose methylation triggers proteasomal rather than autophagic degradation, linking PRMT9 to mitochondrial dysfunction in a Parkinson's model.

    Evidence Co-IP, in vitro methylation, R29 mutagenesis, Trim32-dependent ubiquitination assays and PRMT9 KO/overexpression in MPTP mice

    PMID:42261762

    Open questions at the time
    • How R29 methylation recruits Trim32 not defined
    • Single-lab finding
  11. 2026 Medium

    Demonstrated a dual splicing-and-translation mechanism by which PRMT9 loss overcomes venetoclax resistance in AML.

    Evidence Loss-of-function screens in PDX, RNA splicing analysis of ALG13/ABCC1, protein synthesis assays for MCL1 and pharmacologic inhibition in resistant mouse models

    PMID:42118690

    Open questions at the time
    • Direct methylation substrates driving translational suppression not pinpointed
    • Single-lab finding
  12. 2023 Medium

    Provided chemical-biology tools enabling pharmacologic interrogation and potential targeting of PRMT9.

    Evidence Medicinal chemistry on a PRMT7/PRMT9 dual inhibitor, label-free MS confirmation of cellular inhibition and an AlphaLISA screening assay

    PMID:37560786

    Open questions at the time
    • Inhibitor is not PRMT9-selective
    • No reported structural coordinates

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single splicing-associated methyltransferase coordinates its nuclear splicing role with its diverse cytoplasmic/mitochondrial signaling substrates, and what governs substrate choice and subcellular partitioning, remains unresolved.
  • No structural model explaining recognition of structurally unrelated substrates
  • Regulation of PRMT9 localization between nucleus and mitochondria undefined
  • Relative in vivo contribution of each non-SF3B2 substrate not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 9 GO:0140096 catalytic activity, acting on a protein 5 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 1
Partners
DUSP26HSPA8MAVSSF3B2SF3B4SMNSTAT1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 PRMT9 is a type II protein arginine methyltransferase that directly methylates SAP145 (SF3B2) at arginine 508, producing monomethylated arginine (MMA) and symmetric dimethylarginine (SDMA). This methylation creates a binding site for the Tudor domain of the SMN (Survival of Motor Neuron) protein, linking PRMT9 to U2 snRNP maturation. PRMT9 was also found to associate with SAP49 as a binding partner. In vitro methyltransferase assay, Co-immunoprecipitation, mass spectrometry, site-directed mutagenesis (Arg508), RNA-seq upon PRMT9 knockdown Nature communications High 25737013
2015 PRMT9 requires its C-terminal duplicated methyltransferase domain and unique residues in the double E loop for activity. Unlike other PRMTs, a peptide containing the methylatable Arg-508 of SF3B2 is not recognized by PRMT9 in vitro — the full protein context is required. Moving Arg-508 within its sequence abolishes methylation. PRMT9 and PRMT5 have distinct, non-redundant substrate specificities for SDMA formation; loss of PRMT5 in mouse embryo fibroblasts causes near-complete loss of SDMA, indicating PRMT5 is the primary SDMA-forming enzyme in those cells. Site-directed mutagenesis of PRMT9 and SF3B2, in vitro methyltransferase assays with peptides and full-length protein, PRMT5 knockout mouse embryo fibroblasts The Journal of biological chemistry High 25979344
2006 FBXO11 (designated PRMT9) contains canonical PRMT domains and, when immunopurified from HeLa cells or expressed in E. coli, exhibits arginine methyltransferase activity producing MMA, SDMA, and ADMA on arginine residues. Immunopurification from HeLa cells, recombinant expression in E. coli, in vitro methyltransferase activity assay Biochemical and biophysical research communications Medium 16487488
2017 C. elegans PRMT-9 (ortholog of human PRMT9) produces SDMA and MMA on SFTB-2, the C. elegans ortholog of human SF3B2, demonstrating conserved substrate specificity across species. C. elegans PRMT-9 is biochemically indistinguishable from its human ortholog. Biochemical characterization with in vitro methyltransferase assays on recombinant substrates Biochemistry Medium 28441492
2022 PRMT9 directly binds MAVS and catalyzes arginine methylation at Arg41 and Arg43 of MAVS. In resting cells, this modification inhibits MAVS aggregation and prevents autoactivation of innate immune signaling. Upon viral infection, PRMT9 dissociates from the mitochondria, enabling MAVS aggregation and antiviral signaling. Co-immunoprecipitation, in vitro methyltransferase assay, site-specific mutagenesis, live-cell imaging/fractionation of mitochondrial localization, MAVS aggregation assay Nature communications High 36028484
2023 PRMT9 targets HSPA8 and catalyzes arginine methylation at R76 and R100 of HSPA8, which inhibits ferroptosis in hepatocellular carcinoma cells. HSPA8 overexpression upregulates CD44, and CD44 knockdown reverses the ferroptosis inhibition caused by PRMT9 overexpression, placing PRMT9 upstream of HSPA8 and CD44 in a ferroptosis-suppressive pathway. Co-immunoprecipitation, site-specific arginine methylation assay, genetic overexpression/knockdown, in vivo tumor models, transcriptome profiling Journal of translational medicine Medium 37715221
2024 PRMT9 methylation of SF3B2 at R508 controls a methylation-sensitive protein-RNA interaction between SF3B2 R508 and the pre-mRNA anchoring site (a cis-regulatory element critical for RNA splicing). Knockout of Prmt9 in hippocampal neurons causes alternative splicing of ~1900 genes, resulting in aberrant synapse development and impaired learning and memory. The intellectual disability-associated G189R mutation abolishes PRMT9 methyltransferase activity and reduces protein stability. SF3B2 is established as the primary methylation substrate of PRMT9 in vivo using SF3B2 arginine methylation-deficient mouse models. Conditional knockout mouse, G189R knock-in/expression, RNA-seq, electrophysiology, behavioral testing, SF3B2 R508 methylation-deficient mouse model, protein-RNA interaction assays Nature communications High 38561334
2024 PRMT9 ablation in AML cells decreases arginine methylation of regulators of RNA translation and the DNA damage response, suppresses cell survival, promotes DNA damage, and activates cGAS, triggering a type I interferon response. Genetically activating cGAS in AML cells blocks leukemogenesis, and PRMT9 inhibition synergizes with anti-PD1 in eradicating AML. Genetic ablation (KO) in AML cell lines and PDX models, cGAS activation assay, type I IFN measurement, anti-PD1 combination in vivo Nature cancer Medium 38413714
2026 PRMT9 directly binds STAT1 and catalyzes symmetric dimethylation at R588 and R736. This modification promotes STAT1 ubiquitination and recognition by SQSTM1/p62 and NDP52/CALCOCO2 autophagy receptors, leading to selective autophagic (lysosomal) degradation of STAT1 and suppression of M1-like macrophage polarization. Macrophage-specific PRMT9 knockout enhances M1-like polarization and exacerbates cardiac damage after MI. Co-immunoprecipitation, immunoprecipitation/mass spectrometry, site-directed methylation assay (R588, R736), macrophage-specific KO mouse, flow cytometry, transcriptome analysis, AAV-mediated overexpression in vivo Circulation High 41669821
2026 PRMT9 directly interacts with DUSP26 and catalyzes arginine methylation at R29 of DUSP26. This methylation promotes polyubiquitination and proteasomal degradation of DUSP26 mediated by Trim32, leading to mitochondrial dysfunction and dopaminergic neurodegeneration in a Parkinson's disease model. Co-immunoprecipitation, in vitro methyltransferase assay, site-directed mutagenesis (R29), ubiquitination assay, PRMT9 KO/overexpression in MPTP mouse model, mitochondrial function assays Advanced science Medium 42261762
2026 PRMT9 ablation disrupts RNA splicing by inducing exon-skipping of mRNA encoding ALG13, downregulating the VEN-efflux transporter ABCC1, and suppresses protein synthesis to reduce short-lived oncoproteins such as MCL1, thereby re-sensitizing venetoclax-resistant AML cells to treatment. Loss-of-function screens in PDX cells, RNA splicing analysis, genetic ablation, pharmacologic PRMT9 inhibition in resistant mouse models, protein synthesis assay Blood Medium 42118690
2023 A PRMT7/PRMT9 dual inhibitor was identified and its binding mode to both enzymes was characterized. Label-free quantification mass spectrometry confirmed significant inhibition of PRMT9 activity in cells. An AlphaLISA assay was established for screening PRMT9 inhibitors. Medicinal chemistry, label-free quantification mass spectrometry, AlphaLISA assay Journal of medicinal chemistry Medium 37560786

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 PRMT9 is a type II methyltransferase that methylates the splicing factor SAP145. Nature communications 188 25737013
2006 FBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues. Biochemical and biophysical research communications 123 16487488
2018 PRMT9 promotes hepatocellular carcinoma invasion and metastasis via activating PI3K/Akt/GSK-3β/Snail signaling. Cancer science 100 29603830
2015 Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2. The Journal of biological chemistry 85 25979344
2017 MiRNA-543 promotes osteosarcoma cell proliferation and glycolysis by partially suppressing PRMT9 and stabilizing HIF-1α protein. Oncotarget 61 27911265
2022 The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation. Nature communications 39 36028484
2023 Arginine methylation of HSPA8 by PRMT9 inhibits ferroptosis to accelerate hepatitis B virus-associated hepatocellular carcinoma progression. Journal of translational medicine 36 37715221
2024 Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity. Nature cancer 29 38413714
2017 Caenorhabditis elegans PRMT-7 and PRMT-9 Are Evolutionarily Conserved Protein Arginine Methyltransferases with Distinct Substrate Specificities. Biochemistry 16 28441492
2024 Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing. Nature communications 13 38561334
2023 Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor. Journal of medicinal chemistry 13 37560786
2023 Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report. Medicine 5 36820582
2026 Macrophage PRMT9 Ameliorates Acute Myocardial Infarction by Promoting Symmetric Dimethylation and Degradation of STAT1. Circulation 0 41669821
2026 Targeting PRMT9 Overcomes Venetoclax Resistance in AML by Modulating Splicing and Inhibiting Translation. Blood 0 42118690
2026 PRMT9 Aggravated Dopaminergic Neurodegeneration in Parkinson's Disease Model by Facilitating the Degradation of DUSP26 and Inducing Mitochondrial Dysfunction. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42261762
2025 Bi-allelic PRMT9 loss-of-function variants cause a syndromic form of intellectual disability. American journal of human genetics 0 41260215
2025 m6A-Mediated Stabilization of PRMT9 mRNA by IGF2BP1 Drives Proliferation and Metastasis in Lung Adenocarcinoma. Analytical cellular pathology (Amsterdam) 0 41394407

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