Affinage

MRPL4

Large ribosomal subunit protein uL4m · UniProt Q9BYD3

Round 2 corrected
Length
311 aa
Mass
34.9 kDa
Annotated
2026-04-28
48 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MRPL4 (uL4m) is a structural component of the mitochondrial large ribosomal subunit (mt-LSU) that functions both in mitochondrial translation and as a conserved activator of Notch signaling. Cryo-EM resolved MRPL4 as one of 48 proteins in the human mt-LSU, and quantitative mitochondrial proteomics and proximity labeling confirmed its mitochondrial matrix localization and assembly into the mt-LSU complex (PMID:25278503, PMID:34800366, PMID:32877691). Gene disruption in yeast, mouse, and zebrafish demonstrates that MRPL4 is essential for viability, with loss causing lethality or severe developmental defects including disrupted intestinal growth (PMID:7828914, PMID:32987154, PMID:41709118). Independent of its ribosomal function, MRPL4 physically interacts with the WD40 repeat protein Wap and is required in Notch signal-receiving cells for target gene transcription—a non-canonical role conserved from Drosophila to zebrafish to human, as demonstrated by cross-species rescue and genetic epistasis (PMID:37009823, PMID:41709118).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1995 Medium

    Establishing that MRPL4 is a nuclear-encoded mitochondrial ribosomal protein whose function extends beyond mitochondrial translation, as yeast MRP-L4 disruption caused lethality even on fermentable carbon sources, hinting at additional essential roles.

    Evidence Gene cloning and targeted disruption with growth phenotype analysis on fermentable and non-fermentable carbon sources in S. cerevisiae

    PMID:7828914

    Open questions at the time
    • The extra-ribosomal essential function in yeast was not molecularly defined
    • No mammalian data at this stage
  2. 2014 High

    High-resolution structural determination placed MRPL4 as a bona fide subunit of the mammalian mt-LSU, defining its position within the 48-protein large subunit architecture.

    Evidence Single-particle cryo-EM of the human mitoribosome at 3.4 Å resolution

    PMID:25278503

    Open questions at the time
    • Functional consequences of MRPL4 loss in mammalian cells not tested
    • No information on possible extra-ribosomal roles in metazoans
  3. 2020 Medium

    Systematic expression and knockout data across mouse MRP genes established that MRPL4 is ubiquitously expressed during embryogenesis and essential for viability with no redundancy among family members, while proximity labeling confirmed its physical neighbors as other mt-LSU subunits in human cells.

    Evidence RNA expression profiling across mouse developmental stages; BioID proximity-dependent biotinylation with mass spectrometry in human cells

    PMID:32877691 PMID:32987154

    Open questions at the time
    • Whether lethality is due solely to loss of mitochondrial translation or includes non-canonical functions was unresolved
    • Proximity labeling does not distinguish stable complex membership from transient interactions
  4. 2023 High

    A non-canonical function of MRPL4 was uncovered: it physically interacts with the WD40 protein Wap and is required specifically in Notch signal-receiving cells for transcription of Notch target genes during Drosophila wing development, independent of mitochondrial translation, with human MRPL4 able to rescue the fly mutant phenotype.

    Evidence Genetic epistasis, co-immunoprecipitation with Wap, Notch transcriptional reporters, and cross-species rescue in Drosophila

    PMID:37009823

    Open questions at the time
    • Mechanism by which MRPL4–Wap interaction activates Notch target transcription is unknown
    • Whether MRPL4 acts in the nucleus or cytoplasm for this function was not determined
    • Endogenous MRPL4–Wap interaction not validated in mammalian cells
  5. 2026 High

    The MRPL4–Notch axis was validated in a vertebrate model: zebrafish mrpl4 knockout disrupted intestinal development and epithelial integrity with concomitant Notch downregulation, and genetic reactivation of Notch partially rescued the defect, confirming that MRPL4 operates upstream of Notch signaling in vivo.

    Evidence mrpl4 knockout zebrafish with histological, molecular, and genetic rescue analysis of intestinal phenotype

    PMID:41709118

    Open questions at the time
    • Whether MRPL4 interacts with a vertebrate Wap ortholog to activate Notch was not tested
    • Relative contribution of translational versus non-canonical function to intestinal phenotype not disentangled
    • Mammalian in vivo validation of the Notch-promoting role is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which MRPL4 activates Notch target gene transcription—including whether it translocates to the nucleus, the identity of its mammalian binding partner analogous to Wap, and how this function is coordinated with its mitoribosomal role—remains unresolved.
  • No structural or biochemical data on the MRPL4–Wap interface
  • Subcellular site of MRPL4's non-canonical activity not determined
  • No separation-of-function mutant distinguishing ribosomal from Notch roles

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 GO:0005198 structural molecule activity 1
Partners
WAP
Complex memberships
mitochondrial large ribosomal subunit (mt-LSU)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The yeast nuclear gene MRP-L4 encodes the mitochondrial ribosomal protein YmL4, a 319-amino-acid protein with a 14-aa N-terminal signal peptide cleaved upon mitochondrial import. Gene disruption showed MRP-L4 is essential not only for growth on non-fermentable carbon sources (mitochondrial function) but also for growth on fermentable carbon sources, indicating additional cytosolic and/or mitochondrial functions beyond mitochondrial protein biosynthesis. Gene cloning, gene disruption (knockout), growth phenotype analysis on fermentable and non-fermentable carbon sources Gene Medium 7828914
2014 MRPL4 (uL4m) was identified as one of 48 proteins in the human mitochondrial large ribosomal subunit (mt-LSU) structure resolved by cryo-EM to 3.4 Å resolution, establishing its structural role as a bona fide component of the mammalian mitoribosome large subunit. Single-particle cryo-electron microscopy at 3.4 Å resolution Science High 25278503
2020 Expression analysis of 79 Mrp genes in mouse development showed that Mrpl4 and the other Mrp genes are consistently and broadly expressed throughout early embryogenesis with little stage or tissue specificity. Gene disruption studies across the family revealed that most Mrp genes, including Mrpl4, are essential for viability (early embryonic lethality), indicating no functional redundancy within the family. RNA expression profiling across mouse developmental stages and adult tissues; survey of existing gene disruption data Gene expression patterns : GEP Medium 32987154
2021 Quantitative mitochondrial proteomics placed MRPL4 within the high-confidence human mitochondrial proteome (MitoCoP), confirming its mitochondrial localization and quantifying its abundance as part of the large mitoribosomal subunit complex in human cells. Quantitative mass spectrometry-based mitochondrial proteomics (MitoCoP pipeline) in human cells Cell metabolism Medium 34800366
2020 BioID proximity labeling in human cells placed MRPL4 within the mitochondrial matrix proximity interaction network, identifying its near-neighbors as other large mitoribosomal subunit proteins, consistent with its assembly into the mt-LSU. BioID proximity-dependent biotinylation with 100 mitochondrial baits followed by mass spectrometry in human cells Cell metabolism Medium 32877691
2023 In Drosophila, mRpL4 was shown to be required in Notch signal-receiving cells for target gene transcription during wing development, independent of its role in mitochondrial protein translation. mRpL4 physically interacts with the WD40 repeat protein Wap and genetically cooperates with it to activate Notch signaling target genes. Human MRPL4 can functionally replace fly mRpL4 in this context, demonstrating evolutionary conservation of this non-canonical function. Genetic epistasis analysis, co-immunoprecipitation (physical interaction with Wap), rescue experiments with human MRPL4 in Drosophila, transcriptional reporter assays for Notch target genes EMBO reports High 37009823
2026 Knockout of mrpl4 in zebrafish causes significant defects in intestinal growth and maturation accompanied by disruption of intestinal epithelial integrity and inflammatory responses. Notch signaling is downregulated in mrpl4 mutants, and reactivation of Notch signaling partially rescues the intestinal defects, placing Mrpl4 upstream of Notch signaling in intestinal development. mrpl4 knockout in zebrafish, histological and molecular analysis of intestinal phenotype, Notch signaling pathway analysis, genetic rescue experiments FEBS letters High 41709118

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
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
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
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
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2000 Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome research 392 10810093
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2014 Structure of the large ribosomal subunit from human mitochondria. Science (New York, N.Y.) 262 25278503
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2016 Structure and Function of the Mitochondrial Ribosome. Annual review of biochemistry 217 27023846
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2013 GRSF1 regulates RNA processing in mitochondrial RNA granules. Cell metabolism 198 23473034
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2017 Energy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development. Nature communications 178 28978906
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2010 A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome. The EMBO journal 153 20186120
2015 BioID-based Identification of Skp Cullin F-box (SCF)β-TrCP1/2 E3 Ligase Substrates. Molecular & cellular proteomics : MCP 149 25900982
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2020 Expression analysis of mammalian mitochondrial ribosomal protein genes. Gene expression patterns : GEP 82 32987154
2011 Genome-wide association study for atopy and allergic rhinitis in a Singapore Chinese population. PloS one 72 21625490
2013 The association between polymorphisms in the MRPL4 and TNF-α genes and susceptibility to allergic rhinitis. PloS one 19 23472126
2023 The mitochondrial ribosomal protein mRpL4 regulates Notch signaling. EMBO reports 14 37009823
2019 miR‑126a‑5p‑Dbp and miR‑31a‑Crot/Mrpl4 interaction pairs crucial for the development of hypertension and stroke. Molecular medicine reports 13 31545431
2021 Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer. Cancers 12 34359804
2020 The effects of environmental stressors on candidate aging associated genes. Experimental gerontology 10 32344118
1995 Gene MRP-L4, encoding mitochondrial ribosomal protein YmL4, is indispensable for proper non-respiratory cell functions in yeast. Gene 10 7828914
2022 Proteomics reveals MRPL4 as a high-risk factor and a potential diagnostic biomarker for prostate cancer. Proteomics 8 36059095
2023 Multiple genes encoding mitochondrial ribosomes are downregulated in brain and blood samples of individuals with schizophrenia. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 5 37158323
2024 Comprehensive genotyping analysis of single nucleotide polymorphisms responsible for beef marbling in Japanese Black cattle. BMC genomic data 2 38336623
2024 MicroRNA-2861 regulates the proliferation and apoptosis of human retinal vascular endothelial cells treated with high glucose by targeting NDUFB7. Heliyon 2 39170385
2025 A Six-Gene Signature Related to Mitochondrial Dysfunction as a Potential Diagnostic Biomarker for Sarcopenia. Biotechnology and applied biochemistry 1 41318970
2023 Epigenetic signature discriminates lymphatic metastasis in BRAF wild-type thyroid carcinoma: methylation role of GRIK2. Epigenomics 1 37990886
2026 Comprehensive characterization of transcriptional regulation during HCG-induced follicle maturation in mandarin fish (Siniperca chuatsi): Insights from transcriptomics. Animal reproduction science 0 41616541
2026 Mitochondrial protein Mrpl4 is required for zebrafish intestinal development. FEBS letters 0 41709118
2025 Proteomics suggests the role of Cxcl12 secreted by hucMSCs in the treatment of lipopolysaccharide-acute lung injury. Microvascular research 0 40311750
2025 Identification of MAEA protein as a potential target for chemoresistance in osteosarcoma using bioinformatics and proteomic analysis. Frontiers in oncology 0 40989695