Affinage

MRTO4

mRNA turnover protein 4 homolog · UniProt Q9UKD2

Round 2 corrected
Length
239 aa
Mass
27.6 kDa
Annotated
2026-04-28
43 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MRTO4 is a trans-acting ribosome assembly factor that occupies the ribosomal P0-binding site on pre-60S particles to regulate the timing and fidelity of stalk assembly during large ribosomal subunit biogenesis. As a structural paralogue of P0, MRTO4 binds the 25S/28S rRNA GAR domain through its N-terminal domain, preventing premature P0 loading; in the cytoplasm, the phosphatase Yvh1 displaces MRTO4 from pre-60S subunits to allow P0 incorporation and mature stalk formation (PMID:19346338, PMID:19797078, PMID:20083226). MRTO4 localizes predominantly to the nucleolus via rRNA interaction, shuttles between nucleus and cytoplasm, and its C-terminal serines are phosphorylated by CK2 to modulate its behavior during nucleolar stress (PMID:20083226, PMID:26494001). An additional cytoplasmic role has been described in hepatocellular carcinoma cells, where MRTO4 promotes glycolysis by inhibiting aldolase B (ALDOB) (PMID:38778508).

Mechanistic history

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

    The initial identification of MRT4 linked it to mRNA turnover rather than ribosome biogenesis, establishing that loss of this gene specifically impairs mRNA decay in yeast.

    Evidence Genetic screen with ts mutants; Northern blot mRNA decay assays in S. cerevisiae

    PMID:10471698

    Open questions at the time
    • Mechanism connecting MRT4 to mRNA decay was unknown
    • No direct biochemical activity assigned
    • Relationship to ribosome function not yet tested
  2. 2002 Medium

    Proteomic cataloguing placed human MRTO4 in the nucleolus, suggesting a role in ribosome biogenesis or nucleolar RNA metabolism rather than exclusively cytoplasmic mRNA decay.

    Evidence Mass spectrometry of purified HeLa nucleoli

    PMID:11790298

    Open questions at the time
    • No functional characterization accompanied the localization data
    • Relationship to yeast Mrt4 function not established
  3. 2009 High

    Three concurrent studies resolved MRTO4/Mrt4's core mechanism: it is a P0 paralogue that occupies the same rRNA-binding site on pre-60S particles, its N-terminal domain mediates rRNA binding, and the phosphatase Yvh1 displaces it from cytoplasmic pre-60S subunits to enable P0 loading and stalk maturation.

    Evidence TAP purification of pre-60S complexes; sucrose gradient sedimentation; chimeric Mrt4-P0 complementation; Yvh1 deletion and Mrt4 bypass mutagenesis; molecular dynamics simulation

    PMID:19346338 PMID:19789271 PMID:19797078

    Open questions at the time
    • Structural basis of Yvh1-mediated displacement not resolved at atomic level
    • Whether Yvh1 catalytic activity or physical binding drives Mrt4 release was uncertain
    • Human-specific validation of the Yvh1-MRTO4 axis not yet performed
  4. 2010 High

    Human MRTO4 was confirmed as a nucleolar, nucleocytoplasmic-shuttling ribosome maturation factor that binds the large subunit like P0 but cannot substitute for it, and systematic RNAi validated its role in 60S biogenesis in human cells.

    Evidence Fluorescence microscopy with actinomycin D and leptomycin B; ribosome co-sedimentation; systematic RNAi screen with ribosomal protein reporters

    PMID:20083226 PMID:21048991

    Open questions at the time
    • Mechanism of nucleolar retention via rRNA versus protein-protein interactions not fully dissected
    • Contribution to specific pre-rRNA processing steps in human cells unknown
  5. 2011 Medium

    The Mrt4-Yvh1 interaction was shown to underlie diverse YVH1 deletion phenotypes including mRNA decay, glycogen accumulation, and sporulation gene induction, broadening the physiological scope of Mrt4 displacement beyond ribosome assembly.

    Evidence Dominant suppressor screen with Mrt4(G68D); multiple phenotypic assays in S. cerevisiae

    PMID:21474464

    Open questions at the time
    • Whether these pleiotropic phenotypes arise from defective ribosome maturation or separate Mrt4 functions was unresolved
    • No direct test of stalk composition in suppressed strains
  6. 2012 Medium

    UV crosslinking-based interactome capture demonstrated that MRTO4 directly contacts poly(A)+ mRNA in human cells, consistent with an RNA-binding function extending beyond rRNA.

    Evidence UV crosslinking and oligo(dT) capture followed by quantitative mass spectrometry in HeLa cells

    PMID:22658674

    Open questions at the time
    • Identity of bound mRNA targets unknown
    • Functional consequence of mRNA binding not tested
  7. 2015 Medium

    CK2-mediated phosphorylation of the MRTO4 C-terminal acidic extension (S229/S233/S235) was identified as a regulatory modification that modulates MRTO4 behavior during nucleolar stress without altering steady-state localization.

    Evidence In vitro CK2 kinase assay with phosphosite mutagenesis; in vivo phosphorylation detection; fluorescence microscopy under actinomycin D stress

    PMID:26494001

    Open questions at the time
    • Downstream effectors of phosphorylation unknown
    • Whether phosphorylation affects rRNA or pre-60S binding affinity not tested
    • In vivo kinase responsible not confirmed by knockdown/inhibition
  8. 2024 Medium

    A non-ribosomal function was described in hepatocellular carcinoma, where MRTO4 promotes glycolysis and tumor phenotypes by inhibiting ALDOB, expanding MRTO4's roles to metabolic reprogramming.

    Evidence Loss- and gain-of-function experiments with glycolysis measurements, proliferation, apoptosis, and invasion assays in HCC cell lines

    PMID:38778508

    Open questions at the time
    • Mechanism of ALDOB inhibition (direct binding vs. indirect) not established
    • Whether this function is independent of ribosome biogenesis activity is unclear
    • Single-lab finding without in vivo tumor model validation
  9. 2026 High

    Chemical biology targeting of fungal Mrt4's rRNA-binding interface identified species-selective covalent inhibitors engaging C96/C189, validating the Mrt4-rRNA interaction as druggable and revealing that human MRTO4 is insensitive to these compounds due to structural divergence.

    Evidence AIBPP chemical proteomics; fluorescence polarization binding assay; Galleria mellonella and murine candidiasis infection models

    PMID:41781388

    Open questions at the time
    • No high-resolution co-crystal structure of inhibitor-Mrt4 complex
    • Whether human MRTO4 is targetable by alternative scaffolds is unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of Yvh1-mediated MRTO4 displacement in human cells, whether MRTO4's mRNA-binding activity serves a function beyond ribosome assembly, and the molecular mechanism linking MRTO4 to ALDOB inhibition and glycolytic regulation.
  • No atomic-resolution structure of human MRTO4 on a pre-60S particle
  • mRNA targets of MRTO4 remain unidentified
  • ALDOB inhibition mechanism (direct vs. indirect) unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0005198 structural molecule activity 3
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-8953854 Metabolism of RNA 3
Partners
ALDOBCSNK2A1RPLP0RPSAYVH1
Complex memberships
pre-60S ribosomal particle

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 MRT4 was identified as a novel yeast gene required for mRNA turnover; temperature-sensitive mrt4 mutants exhibit defects in decay of multiple mRNAs without a significant defect in protein synthesis, suggesting a specific role in mRNA decay rather than general translation. Genetic screen for mRNA turnover defects; complementation analysis; Northern blot analysis of mRNA decay rates in ts mutants Genetics Medium 10471698
2002 MRTO4 (human Mrt4) was identified as a component of the human nucleolar proteome, establishing its nucleolar localization in human cells. Mass spectrometry-based proteomic analysis of isolated human HeLa cell nucleoli Current biology : CB Medium 11790298
2009 Mrt4 is a nuclear/nucleolar paralogue of the ribosomal stalk protein P0 that binds the same site on 25S rRNA (GAR domain); Mrt4 and P0 cannot bind simultaneously to ribosomes, and Mrt4 controls the position and timing of P0 assembly into pre-60S particles. Loss of Mrt4 causes 60S subunit deficits due to impaired 27S rRNA processing. TAP-tag purification of pre-60S complexes; sucrose gradient sedimentation; rRNA processing analysis; genetic depletion of P0 and Mrt4 Nucleic acids research High 19789271
2009 The dual-specificity phosphatase Yvh1 is required for release of Mrt4 from pre-60S subunits in the cytoplasm; Yvh1 binds pre-60S to displace Mrt4, after which P0 loads to assemble the mature stalk and Yvh1 is released. A Mrt4 mutation at the protein-RNA interface (bypassing Yvh1 requirement) confirmed the mechanism. Genetic deletion of YVH1; sucrose gradient sedimentation; TAP purification of pre-60S particles; mutagenesis of Mrt4 RNA-binding interface The Journal of cell biology High 19797078
2009 The N-terminal domain (first 137 aa) of Mrt4 is sufficient for rRNA binding and can partially replace the RNA-binding domain of P0; a Mrt4-P0 chimera partially complements P0 absence but shows weaker ribosome binding and reduced association of P1/P2 and L12 stalk components. Molecular dynamics simulations showed both proteins bind similarly to rRNA but differ in L12 interaction. Chimeric protein construction; ribosome co-sedimentation; genetic complementation of conditional P0 null mutant; molecular dynamics simulation Nucleic acids research High 19346338
2010 Human MRTO4 localizes predominantly to the nucleolus (unlike cytoplasmic P0/P1/P2) and binds the same site on the large ribosomal subunit as P0 but cannot functionally complement P0 absence. Nuclear import of hMrt4 depends on a short N-terminal sequence, and its nucleolar retention occurs via interaction with rRNA rather than a dedicated nucleolus localization signal. Actinomycin D and leptomycin B experiments show hMrt4 shuttles between nucleus and cytoplasm and acts as a trans-acting ribosome maturation factor. Fluorescence microscopy of hybrid hMrt4-P0 proteins; biochemical fractionation; pharmacological inhibition with actinomycin D and leptomycin B; ribosome co-sedimentation The international journal of biochemistry & cell biology High 20083226
2010 RNAi knockdown of the human MRTO4 ortholog in a systematic screen confirmed its functional contribution to 60S ribosomal subunit biogenesis in human cells, consistent with its yeast role. Systematic RNAi screen using fluorescent ribosomal protein reporters and automated image analysis in human cells PLoS biology Medium 21048991
2011 Genetic interaction analysis in yeast showed that the Mrt4(G68D) mutation (at the protein-RNA interface) suppresses all phenotypes caused by YVH1 deletion, including defects in rRNA biogenesis, mRNA decay, glycogen accumulation, and induction of sporulation genes IME2, SPO13, and HOP1, demonstrating that the Mrt4-Yvh1 interaction is essential for these diverse cellular functions. Dominant suppressor genetic screen; yeast growth assays; rRNA processing analysis; mRNA decay assays; glycogen staining; sporulation gene expression analysis Journal of biochemistry Medium 21474464
2012 MRTO4 was identified as a component of the human mRNA-bound proteome by UV crosslinking and oligo(dT) capture in HeLa cells, establishing it as an RNA-binding protein with direct mRNA contacts. Interactome capture — UV crosslinking of RBPs to mRNA followed by oligo(dT) purification and quantitative mass spectrometry Cell Medium 22658674
2015 Human MRTO4 undergoes phosphorylation in vivo; serines S229, S233, and S235 within its acidic C-terminal extension are phosphorylated by CK2 kinase in vitro. This phosphorylation does not alter steady-state subcellular distribution but regulates MRTO4 molecular behavior during actinomycin D-induced nucleolar stress, implicating the C-terminal region as a regulatory element linking ribosome biogenesis to stress response. In vivo phosphorylation detection; in vitro CK2 kinase assay with phosphosite mutagenesis; fluorescence microscopy under nucleolar stress conditions The international journal of biochemistry & cell biology Medium 26494001
2024 MRTO4 promotes glycolysis in hepatocellular carcinoma cells by inhibiting ALDOB (aldolase B); knockdown of MRTO4 reduces glycolytic flux, proliferation, and invasion while increasing apoptosis, and overexpression has opposite effects, placing MRTO4 upstream of ALDOB in metabolic reprogramming. RT-qPCR; Western blotting; CCK8 proliferation assay; TUNEL apoptosis assay; clone formation; Transwell invasion assay; ELISA; glycolysis measurements; loss- and gain-of-function experiments Medical science monitor Medium 38778508
2026 Fungal Mrt4 (CaMrt4) binds rRNA through cysteine residues C96 and C189; cis-fumaramidmycin-derived compounds selectively inhibit CaMrt4-rRNA interaction by covalently engaging both cysteines, disrupting ribosome assembly specifically in fungi without affecting human MRTO4-rRNA interaction, validating Mrt4-rRNA binding as an antifungal target. Active-and-inactive-based protein profiling (AIBPP); chemical-genetic profiling; fluorescence polarization assay; in vivo Galleria mellonella and murine candidiasis models Nature communications High 41781388

Source papers

Stage 0 corpus · 43 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
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
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
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
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
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
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2002 Functional proteomic analysis of human nucleolus. Molecular biology of the cell 391 12429849
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2009 Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Science signaling 207 19738201
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2010 A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export. PLoS biology 172 21048991
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2012 Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription. Molecular & cellular proteomics : MCP 145 22586326
2006 The DNA sequence and biological annotation of human chromosome 1. Nature 144 16710414
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2014 The central role of EED in the orchestration of polycomb group complexes. Nature communications 131 24457600
2020 PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase. Nature chemical biology 129 32989298
2009 Ribosome stalk assembly requires the dual-specificity phosphatase Yvh1 for the exchange of Mrt4 with P0. The Journal of cell biology 96 19797078
2009 Role and dynamics of the ribosomal protein P0 and its related trans-acting factor Mrt4 during ribosome assembly in Saccharomyces cerevisiae. Nucleic acids research 64 19789271
1999 Temperature-sensitive mutations in the Saccharomyces cerevisiae MRT4, GRC5, SLA2 and THS1 genes result in defects in mRNA turnover. Genetics 54 10471698
2009 The amino terminal domain from Mrt4 protein can functionally replace the RNA binding domain of the ribosomal P0 protein. Nucleic acids research 44 19346338
2010 Subcellular localization of ribosomal P0-like protein MRT4 is determined by its N-terminal domain. The international journal of biochemistry & cell biology 18 20083226
2015 Molecular behavior of human Mrt4 protein, MRTO4, in stress conditions is regulated by its C-terminal region. The international journal of biochemistry & cell biology 9 26494001
2011 Genetic interactions of ribosome maturation factors Yvh1 and Mrt4 influence mRNA decay, glycogen accumulation, and the expression of early meiotic genes in Saccharomyces cerevisiae. Journal of biochemistry 9 21474464
2009 [Influence of Tripterygium wilfordii on the expression of spermiogenesis related genes Herc4, Ipo11 and Mrto4 in mice]. Yi chuan = Hereditas 8 19819847
2024 MRTO4 Enhances Glycolysis to Facilitate HCC Progression by Inhibiting ALDOB. Medical science monitor : international medical journal of experimental and clinical research 7 38778508
2022 Recombinant expression and biophysical characterization of Mrt4 protein that involved in mRNA turnover and ribosome assembly from Saccharomyces cerevisiae. Bioengineered 5 35387555
2026 Inhibiting Mrt4-rRNA interaction with fumaramidmycin-based derivatives as an antifungal strategy. Nature communications 0 41781388
2025 Integrated multi-omics analysis identifies DARS2, MRTO4, and MRPL37 as novel biomarkers and potential therapeutic targets for bladder cancer. Discover oncology 0 41364147
2024 Roles of WDR12 and MRTO4 genes in colorectal cancer. Medicine 0 39969382