Affinage

MED31

Mediator of RNA polymerase II transcription subunit 31 · UniProt Q9Y3C7

Round 2 corrected
Length
131 aa
Mass
15.8 kDa
Annotated
2026-04-28
40 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MED31 is the smallest and most evolutionarily ancient subunit of the Mediator coactivator complex, essential for both basal and activator-dependent RNA polymerase II transcription across eukaryotes (PMID:10024883, PMID:11559591, PMID:15356001). In mammals, Med31 promotes transcription of genes required for cell proliferation and chondrogenesis during embryonic development, and sustains self-renewal and adipogenic differentiation in adult mesenchymal stem cells (PMID:20347762, PMID:30006772). Beyond its nuclear transcriptional role, MED31 undergoes Elmo1-dependent monoubiquitination and cytoplasmic relocalization, which specifically modulates cytokine gene expression (Il10, Il33) during macrophage responses to bacterial infection (PMID:23273896). MED31 protein levels are post-transcriptionally regulated by miR-1, and MED31 knockdown suppresses MET proto-oncogene expression and downstream HGF signaling in osteosarcoma cells (PMID:24969180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 High

    Identification of MED31 as a subunit of the human Mediator-like SMCC complex established that a yeast SOH1 homolog is conserved in mammalian transcriptional coactivator machinery capable of both repressing and enhancing activator-dependent transcription.

    Evidence Biochemical purification of SMCC complex with mass spectrometry identification and in vitro transcription assays

    PMID:10024883

    Open questions at the time
    • Specific contribution of MED31 versus other SMCC subunits not dissected
    • No loss-of-function data for MED31 alone
  2. 2001 High

    Demonstrating that Mediator depletion abolishes transcription on all tested promoters established MED31-containing Mediator as a general transcription factor required for basal and activated transcription, not merely an activator-specific cofactor.

    Evidence Antibody depletion of Mediator from crude extracts followed by in vitro transcription on TATA-containing and TATA-less promoters

    PMID:11559591

    Open questions at the time
    • Depletion removed entire Mediator rather than MED31 alone
    • In vitro system may not recapitulate all in vivo regulation
  3. 2004 High

    Phylogenetic and biochemical analyses across yeast species established MED31 as among the most ancient Mediator subunits, predating the canonical Pol II CTD heptapeptide repeat, and confirmed its stable incorporation into Mediator in multiple organisms.

    Evidence Mediator complex purification from S. pombe and S. cerevisiae; bioinformatic phylogenetic reconstruction

    PMID:15175163 PMID:15356001

    Open questions at the time
    • Structural basis for MED31 integration into the complex not resolved
    • Function of MED31 outside of Mediator context unexplored
  4. 2007 Medium

    Genome-wide profiling of Med31 deletion in S. pombe revealed that Med31 acts as a coactivator downstream of Sep1-Ace2 transcription factors for cell separation genes, establishing a specific gene-regulatory role beyond general transcription.

    Evidence Microarray profiling of sep10 (Med31) deletion mutants with genetic epistasis analysis in S. pombe

    PMID:17922236

    Open questions at the time
    • Mechanism by which Med31 is recruited to Sep1-Ace2 target promoters not determined
    • Single organism, single lab
  5. 2010 High

    A mouse point mutation causing Med31 protein degradation produced late-gestation lethality with reduced cell proliferation and defective chondrogenesis, directly demonstrating that Med31 promotes transcription of cell cycle (Cdc2) and cartilage differentiation (Sox9, Col2a1) genes in vivo.

    Evidence ENU mutagenesis screen, western blot for protein stability, embryonic fibroblast proliferation assays, immunohistochemistry for cell cycle and chondrogenic markers

    PMID:20347762

    Open questions at the time
    • Direct transcriptional targets genome-wide not identified in mammalian context
    • Whether phenotypes reflect Mediator destabilization versus MED31-specific functions unclear
  6. 2012 High

    Discovery that cytoplasmic Elmo1 physically interacts with MED31, promotes its monoubiquitination and cytoplasmic relocalization, and together with MED31 regulates Il10 and Il33 expression during Salmonella infection revealed a non-canonical regulatory axis for a Mediator subunit outside the nucleus.

    Evidence Reciprocal Co-IP, subcellular fractionation, ubiquitination assays, gene expression analysis in primary macrophages during bacterial infection

    PMID:23273896

    Open questions at the time
    • Ubiquitin ligase responsible for MED31 monoubiquitination not identified
    • Whether cytoplasmic MED31 has transcription-independent functions unknown
    • Mechanism linking MED31 ubiquitination to cytokine gene regulation not resolved
  7. 2014 Medium

    MED31 was placed upstream of MET oncogene signaling via miR-1-mediated post-transcriptional regulation, linking Mediator subunit levels to oncogenic pathway activity in osteosarcoma cells; concurrently, EM structural mapping resolved MED31's position within the Mediator architecture.

    Evidence Luciferase 3′UTR reporter assay, siRNA knockdown with MET pathway readouts; EM with antibody labeling for subunit localization

    PMID:24882805 PMID:24969180

    Open questions at the time
    • Whether MED31 directly regulates MET transcription or acts indirectly through Mediator integrity is unresolved
    • High-resolution atomic structure of MED31 within Mediator not yet available at this time point
  8. 2018 Medium

    MED31 knockdown in human mesenchymal stem cells impaired both self-renewal and adipogenic differentiation, extending its proliferative role to adult stem cell homeostasis.

    Evidence siRNA knockdown with proliferation assays, lipid staining for adipogenesis, qRT-PCR for lineage markers in hMSCs

    PMID:30006772

    Open questions at the time
    • Transcriptional targets mediating self-renewal versus differentiation not identified
    • No genetic rescue performed
    • Single lab, no in vivo validation
  9. 2019 High

    In Tetrahymena, Med31 ChIP-seq demonstrated global association with transcribed genes and knockdown caused ectopic developmental gene expression, while Med31 localization to meiotic micronuclei implicated Mediator in ncRNA transcription, extending the functional repertoire beyond protein-coding gene regulation.

    Evidence Endogenous tagging, AP-MS, ChIP-seq, RNAi with RNA-seq, immunofluorescence in Tetrahymena

    PMID:31280994

    Open questions at the time
    • Whether ncRNA transcription role is conserved in metazoans is unknown
    • Mechanism of Med31 recruitment to specific loci not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase for MED31 monoubiquitination, the functional significance of cytoplasmic MED31, whether MED31 has Mediator-independent functions, and high-resolution structural details of MED31 contacts within the human Mediator complex.
  • E3 ligase for MED31 monoubiquitination not identified
  • No Mediator-independent function demonstrated
  • Genome-wide direct target identification in mammalian cells lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0140223 general transcription initiation factor activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 1 R-HSA-168256 Immune System 1
Partners
ELMO1MED7SOX9
Complex memberships
Mediator complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The human SOH1 homolog (MED31) was identified as a component of the SMCC (SRB/MED-containing cofactor) complex, a human Mediator-like complex containing homologs of yeast mediator/holoenzyme components including SOH1 and NUT2, capable of repressing or enhancing activator-dependent transcription and showing direct activator interactions independent of the RNA polymerase II CTD. Biochemical purification, mass spectrometry identification of complex subunits, in vitro transcription assays Molecular cell High 10024883
2001 Human Mediator (containing MED31/SOH1) is required for basal RNA polymerase II transcription; antibody depletion of Mediator components abolished transcription on all genes tested, on both TATA-containing and TATA-less promoters, in the presence and absence of activators. Monoclonal antibody depletion from crude cell extracts, in vitro transcription assays, immunopurification EMBO reports High 11559591
2004 Soh1/MED31 is a stable component of the Mediator complex in both Schizosaccharomyces pombe and Saccharomyces cerevisiae, and bioinformatic analysis places the Soh1/MED31 family as among the most evolutionarily ancient Mediator subunits, predating the canonical heptapeptide repeat structure of the RNA Pol II CTD. Biochemical purification of Mediator complex, co-purification/stable association demonstrated, bioinformatic phylogenetic analysis The Journal of biological chemistry High 15356001
2004 MED31 (NUT2 in prior nomenclature) was identified as one of the consensus mammalian Mediator subunits, present across six independent immunoaffinity-purified Mediator preparations analyzed by MudPIT proteomics. Multidimensional protein identification technology (MudPIT), six independent Mediator immunopurifications Molecular cell High 15175163
2007 In S. pombe, Med31 (encoded by sep10+) controls large sets of genes involved in cell separation, acting as a coactivator for Sep1-Ace2-dependent cell separation genes; Med31 deletion disrupts cell separation without affecting sep1+ or ace2+ expression, placing Med31 downstream of these transcription factors as a coactivator. Genome-wide gene expression profiling of sep10 deletion mutants, genetic epistasis analysis Molecular genetics and genomics Medium 17922236
2010 Mouse Med31 is required for embryonic growth and cell proliferation; a point mutation causing Med31 protein degradation results in late-gestation lethality, reduced proliferating cells in rapidly expanding tissues, severe proliferation defect in cultured embryonic fibroblasts, reduced Cdc2 (cell cycle protein) levels, and defective chondrogenesis with loss of Sox9 and Col2a1 expression, indicating Med31 promotes transcription of genes required for growth and proliferation. ENU mutagenesis screen, genetic mapping, protein degradation confirmed by western blot, embryonic fibroblast proliferation assays, immunohistochemistry for cell cycle markers and chondrogenic markers Developmental biology High 20347762
2012 MED31 physically interacts with the cytoplasmic engulfment protein Elmo1; this interaction increases the cytoplasmic localization of normally nuclear MED31 and promotes monoubiquitination of Med31, identifying ubiquitination as a novel post-translational modification of Med31. During Salmonella infection in primary macrophages, Elmo1 and Med31 together specifically regulate expression of cytokine genes Il10 and Il33. Co-immunoprecipitation, subcellular fractionation/localization experiments, ubiquitination assays, gene expression monitoring in primary macrophages during Salmonella infection Current biology High 23273896
2014 MED31 is a direct target of miR-1 in osteosarcoma cells, validated by luciferase reporter assay; knockdown of Med31 suppresses osteosarcoma cell proliferation and reduces expression of MET proto-oncogene and blocks downstream HGF-stimulated MET signaling, placing Med31 upstream of MET pathway activation. Luciferase reporter assay (3'UTR target validation), siRNA knockdown, cell proliferation assays, western blotting for MET and downstream signaling Oncology reports Medium 24969180
2014 Electron microscopy structures of yeast and human Mediator complexes with comprehensive subunit localization experiments provided the first accurate EM-based structural mapping of Mediator subunit positions and revealed that large-scale Mediator conformational rearrangements occur at interfaces between Mediator modules during transcription initiation. Electron microscopy, subunit localization by antibody labeling and crosslinking, biochemical analyses Cell High 24882805
2018 MED31 knockdown in human mesenchymal stem cells (hMSCs) using siRNA reduces self-renewal capacity (assessed by cell assays and gene expression) and impairs adipogenic differentiation, evidenced by diminished lipid vesicle formation and reduced adipogenic marker expression, demonstrating a role for MED31 in maintaining adult stem cell homeostasis. siRNA-mediated knockdown, cell proliferation/self-renewal assays, adipogenesis assays (lipid staining), qRT-PCR for lineage markers Molecular biology reports Medium 30006772
2019 In Tetrahymena thermophila, endogenously tagged Med31 physically associates with >20 proteins including canonical Mediator subunits identified by AP-MS; Med31 ChIP-seq shows global association with transcribed genes; Med31 knockdown causes ectopic expression of developmental genes for programmed DNA rearrangements; and Med31 localizes to meiotic micronuclei implicating Mediator in ncRNA transcription. Endogenous tagging, affinity purification coupled with mass spectrometry (AP-MS), ChIP-seq, RNAi knockdown with RNA-seq, indirect immunofluorescence Current biology High 31280994
2026 ELMO1 methylation interacts with Med31 in H. pylori-infected gastric cancer cells (AGS); Co-immunoprecipitation confirmed ELMO1-Med31 protein interaction; this interaction drives M2 macrophage polarization and promotes epithelial-mesenchymal transition (EMT) and intestinal metaplasia in H. pylori-infected cells. Co-immunoprecipitation, methylation-specific PCR, co-culture experiments, western blotting, cell viability/migration assays Scientific reports Medium 41535333

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell host & microbe 627 18976975
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2000 Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome research 392 10810093
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
1999 Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. Molecular cell 353 10198638
2004 A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Molecular cell 339 15383276
2011 Human mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 281 21729782
2004 A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology. Molecular cell 265 15175163
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
1999 A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Molecular cell 233 10024883
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2013 The protein interaction landscape of the human CMGC kinase group. Cell reports 174 23602568
2014 Subunit architecture and functional modular rearrangements of the transcriptional mediator complex. Cell 163 24882805
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2005 MED1/TRAP220 exists predominantly in a TRAP/ Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription. Molecular cell 122 15989967
2001 Novel critical role of a human Mediator complex for basal RNA polymerase II transcription. EMBO reports 107 11559591
2004 The Soh1/MED31 protein is an ancient component of Schizosaccharomyces pombe and Saccharomyces cerevisiae Mediator. The Journal of biological chemistry 37 15356001
2018 Mediator subunit MED31 is required for radial patterning of Arabidopsis roots. Proceedings of the National Academy of Sciences of the United States of America 36 29844159
2010 The Mediator complex protein Med31 is required for embryonic growth and cell proliferation during mammalian development. Developmental biology 26 20347762
2021 Exosome-Mediated Transfer of circ-GLIS3 Enhances Temozolomide Resistance in Glioma Cells Through the miR-548m/MED31 Axis. Cancer biotherapy & radiopharmaceuticals 20 34762494
2014 MicroRNA-1 functions as a potential tumor suppressor in osteosarcoma by targeting Med1 and Med31. Oncology reports 17 24969180
2007 Genomic expression patterns in cell separation mutants of Schizosaccharomyces pombe defective in the genes sep10 ( + ) and sep15 ( + ) coding for the Mediator subunits Med31 and Med8. Molecular genetics and genomics : MGG 17 17922236
2019 The Med31 Conserved Component of the Divergent Mediator Complex in Tetrahymena thermophila Participates in Developmental Regulation. Current biology : CB 15 31280994
2012 A link between the cytoplasmic engulfment protein Elmo1 and the Mediator complex subunit Med31. Current biology : CB 15 23273896
2018 MED31 involved in regulating self-renewal and adipogenesis of human mesenchymal stem cells. Molecular biology reports 7 30006772
2026 Interaction between ELMO1 DNA methylation and Med31 promotes H. pylori-induced gastric cancer EMT and intestinal metaplasia via M2 polarization. Scientific reports 0 41535333