Affinage

RPL38

Large ribosomal subunit protein eL38 · UniProt P63173

Round 2 corrected
Length
70 aa
Mass
8.2 kDa
Annotated
2026-04-28
46 papers in source corpus 12 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RPL38 (eL38) is a small, lysine-rich structural component of the 60S large ribosomal subunit that functions as a selective translational regulator of specific mRNA subsets rather than a general translation factor (PMID:33926116, PMID:15520262). Ribosome profiling after RPL38 knockdown reveals altered translational efficiencies of ~150 mRNAs enriched for transcription regulators and Hox pathway genes, while broad transcriptomic remodeling affects p53 signaling, calcium metabolism, and osteogenesis-related programs (PMID:33926116, PMID:33675855). Beyond its ribosomal role, RPL38 directly interacts with the m6A methyltransferase METTL3 to promote epitranscriptomic modification of SOCS2 mRNA, linking it to JAK2/STAT3 inflammatory signaling in chondrocytes (PMID:35596790). Haploinsufficiency of Rpl38 in mice (Tail-short mutant) causes conductive hearing loss through middle ear over-ossification and chronic otitis media, rescued by Rpl38 cDNA transgene, while in Drosophila its depletion blocks spermatogonial differentiation via loss of bam expression (PMID:21062742, PMID:39187660).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1978 High

    Identification of RPL38 as a bona fide protein component of the 60S large ribosomal subunit established its existence and basic biochemical properties, answering whether eukaryotic ribosomes contain this discrete polypeptide.

    Evidence Ion-exchange chromatography and SDS-PAGE of rat liver 60S subunit proteins

    PMID:621213

    Open questions at the time
    • No functional data; purely compositional assignment
    • Precise molecular weight and sequence unknown
  2. 1991 High

    Determination of the full primary sequence (69 amino acids, 8,081 Da) and gene copy number answered the molecular identity question and revealed RPL38 as one of the smallest ribosomal proteins with an unusually high lysine content.

    Evidence cDNA cloning and sequencing from rat; Southern and Northern blot

    PMID:1840484

    Open questions at the time
    • No information on RPL38's position within the ribosome
    • Functional role uncharacterized
  3. 1997 Medium

    Cloning of human RPL38 revealed perfect conservation (100% amino acid identity with rat), implying strong functional constraint, and identified an unusual processed pseudogene inserted into the angiotensin II receptor promoter.

    Evidence cDNA cloning from human; Southern blot genomics

    PMID:9375793

    Open questions at the time
    • Functional significance of extreme conservation unexplained
    • Pseudogene impact on AT1R regulation not tested
  4. 2004 High

    Genetic analysis in Drosophila demonstrated that RPL38 haploinsufficiency produces classic Minute phenotypes plus paradoxical cell-size-dependent organ overgrowth, establishing that RPL38 dosage specifically controls cell and organ size beyond simple translational housekeeping.

    Evidence Forward genetic screen mapping RpL38 point mutations; wing and bristle morphometry across multiple alleles

    PMID:15520262

    Open questions at the time
    • Downstream translational targets mediating growth phenotype unknown
    • Whether phenotype is specific to eL38 or general to 60S haploinsufficiency not resolved
  5. 2010 High

    The Tail-short mouse mutant causally linked Rpl38 loss to conductive hearing loss through middle ear over-ossification and chronic otitis media, with full transgenic rescue proving gene-specific causality and establishing the first mammalian disease model for RPL38 deficiency.

    Evidence Genetic mapping, ABR/DPOAE audiometry, histology, and cDNA transgenic rescue in Ts mice

    PMID:21062742

    Open questions at the time
    • Molecular mechanism connecting reduced RPL38 to ectopic ossification unclear
    • Cell types in which RPL38 acts to prevent middle ear pathology not identified
  6. 2013 High

    Cryo-EM structures of human and Drosophila 80S ribosomes placed eL38 within the 60S subunit at atomic detail, revealing its position among metazoan-specific structural elaborations not present in yeast.

    Evidence High-resolution cryo-EM of human and Drosophila 80S ribosomes

    PMID:23636399

    Open questions at the time
    • How eL38's position relates to its selective translational role unresolved
    • No conformational dynamics data
  7. 2015 High

    Near-atomic (3.6 Å) cryo-EM of the human 80S ribosome refined eL38's molecular context at the subunit interface and near tRNA binding sites, providing a structural basis for understanding potential mRNA-selective functions.

    Evidence Single-particle cryo-EM at 2.9–3.6 Å resolution

    PMID:25901680

    Open questions at the time
    • No direct evidence that eL38's structural position explains mRNA selectivity
    • No mutagenesis of eL38 contact residues performed
  8. 2021 Medium

    Ribosome profiling after RPL38 knockdown demonstrated that eL38 selectively controls translational efficiency of ~150 mRNAs (including Hox-activating transcription factors), while simultaneously reshaping broader transcriptomes, answering whether RPL38 acts as a general or specialized translation factor.

    Evidence siRNA knockdown in HEK293 cells with Ribo-seq and RNA-seq

    PMID:33675855 PMID:33926116

    Open questions at the time
    • Mechanism by which eL38 confers mRNA selectivity (IRES, UTR elements) not defined
    • Results from a single cell type; tissue specificity untested
    • Transcriptomic changes could include indirect effects
  9. 2022 Medium

    Discovery that RPL38 directly binds METTL3 and promotes m6A modification of SOCS2 mRNA revealed a non-ribosomal, epitranscriptomic function regulating JAK2/STAT3 inflammatory signaling in chondrocytes.

    Evidence Co-immunoprecipitation, siRNA knockdown, ELISA, flow cytometry, and in vivo OA mouse model

    PMID:35596790

    Open questions at the time
    • Reciprocal Co-IP or in vitro reconstitution of RPL38-METTL3 complex not shown
    • Whether RPL38-METTL3 interaction occurs on or off the ribosome is unknown
    • Single laboratory; independent replication needed
  10. 2024 High

    Genetic epistasis in Drosophila testes established that RpL38 is essential for spermatogonial differentiation by promoting bam expression, with bam overexpression fully rescuing RpL38-knockdown infertility, thus identifying a specific developmental effector downstream of eL38.

    Evidence RNAi, proteomics, transcriptomics, and bam overexpression rescue in Drosophila

    PMID:39187660

    Open questions at the time
    • Whether RpL38 controls bam at the translational or transcriptional level is not distinguished
    • Mammalian spermatogenesis role not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis of RPL38's mRNA selectivity — whether mediated through specific IRES/UTR elements, ribosome heterogeneity, or extra-ribosomal moonlighting — remains unresolved, as does the relationship between its ribosomal and METTL3-associated functions.
  • No cis-element on target mRNAs identified that confers eL38 dependence
  • Structural basis for mRNA selectivity lacking
  • Ribosomal vs. extra-ribosomal pools of RPL38 not quantified in any tissue

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0045182 translation regulator activity 2
Localization
GO:0005840 ribosome 3 GO:0005829 cytosol 2
Pathway
GO:0005840 ribosome 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2
Partners
METTL3
Complex memberships
80S ribosome (60S large subunit)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1978 RPL38 (L38) was isolated as a protein component of the 60S large ribosomal subunit from rat liver ribosomes by ion-exchange chromatography. Its molecular weight was estimated by SDS-PAGE and its amino acid composition was determined, establishing it as a bona fide structural constituent of the large ribosomal subunit. Ion-exchange chromatography (carboxymethylcellulose/DEAE-cellulose), gel filtration, SDS-PAGE, amino acid composition analysis The Journal of biological chemistry High 621213
1991 The primary amino acid sequence of rat ribosomal protein L38 was determined from cDNA sequences: L38 consists of 69 amino acids (N-terminal Met is co-translationally removed) with a molecular weight of 8,081 Da. Southern blot hybridization indicated 11–13 copies of the L38 gene in the rat genome, and the mRNA is ~450 nucleotides in length. cDNA cloning and sequencing, Southern blot hybridization, Northern blot Biochemical and biophysical research communications High 1840484
1995 Mammalian (rat) ribosomal protein L38 was characterized as a lysine-rich small protein of the 60S subunit, and its amino acid sequence was reviewed in the context of the full complement of 80 rat ribosomal proteins, noting structural motifs including clusters of basic residues and nuclear localization signals common among ribosomal proteins. Comparative sequence analysis, biochemical characterization Biochemistry and cell biology Medium 8722009
1997 The human RPL38 cDNA was cloned, encoding a lysine-rich 69-amino-acid polypeptide identical to rat RPL38 (100% identity). Southern blot analysis showed RPL38 is not a multigene family in humans. An unusual RPL38 processed pseudogene lacking the poly-A tail and entire 5'-UTR was identified in the promoter region of the human type-1 angiotensin II receptor gene, representing an atypical retrotransposition product. cDNA cloning and sequencing, Northern blot, Southern blot Biochimica et biophysica acta Medium 9375793
2004 Heterozygous point mutations in Drosophila RpL38 (located in centric heterochromatin of chromosome 2R, identical to Minute M(2)41A) cause classic Minute phenotypes (small bristles, delayed development) demonstrating haploinsufficiency. Unexpectedly, RpL38(−)/+ adults have abnormally large wings due to increased cell size, placing RpL38 as a regulator of translational control of organ growth. Forward genetic screen, point mutation mapping, wing morphometry, bristle/developmental phenotype scoring Genetics High 15520262
2010 In the mouse Tail-short (Ts) mutant, an 18-kb deletion/insertion disrupts the Rpl38 gene. Rpl38 deficiency causes conductive hearing loss due to middle ear pathology: over-ossification at the round window ridge, ectopic cholesterol crystal deposition, enlarged Eustachian tube, and chronic otitis media with effusion starting ~3 weeks post-birth. Endocochlear potentials and inner ear histology are normal, localizing the defect to the middle ear. Rpl38 protein (~8 kDa) is predominantly expressed in mature erythrocytes. Transgenic rescue with an Rpl38 cDNA fully rescues all Ts phenotypes, proving causality. Genetic mapping, deletion/insertion characterization, auditory brainstem response, distortion-product otoacoustic emissions, endocochlear potential measurement, histology, immunostaining with specific antisera, cDNA transgenic rescue The Journal of biological chemistry High 21062742
2013 Cryo-electron microscopy structures of the human and Drosophila 80S ribosomes determined at high resolution positioned RPL38 (eL38) as a protein component of the 60S large ribosomal subunit, revealing metazoan-specific structural features including additional RNA and protein layers not present in yeast ribosomes. High-resolution cryo-electron microscopy, atomic model building Nature High 23636399
2015 The near-atomic resolution cryo-EM structure (average 3.6 Å, reaching 2.9 Å in stable regions) of the human 80S ribosome placed RPL38 (eL38) within the large 60S subunit, providing detailed information on its molecular context within the human ribosome including subunit interface and tRNA binding site interactions. Single-particle cryo-electron microscopy, atomic model building Nature High 25901680
2021 Knockdown of eL38 (RPL38) in HEK293 cells (~4-fold reduction) significantly altered translational efficiencies of 150 genes as measured by ribosome profiling. Genes with enhanced translation were mainly associated with basic metabolic processes (translation, protein folding, chromosome organization, splicing); genes with reduced translation efficiency included those regulating transcription and Hox gene activation. This established that eL38 specifically modulates the translation of subsets of mRNAs rather than acting as a general translational factor. siRNA knockdown, ribosome profiling (Ribo-seq), next-generation sequencing International journal of molecular sciences Medium 33926116
2021 A ~4-fold knockdown of eL38 (RPL38) mRNA in HEK293 cells caused significant changes in expression of ~1,500 genes at the transcriptional level. Down-regulated genes included those responsible for p53 activity, Ca2+ metabolism, signaling, and cytoskeletal organization. Up-regulated genes included those related to rRNA processing, translation, and developmental disorder-associated genes. This suggests RPL38 insufficiency reorganizes genomic transcription, potentially linking RPL38 balance to osteogenesis-related gene expression and the Tail-short phenotype. siRNA knockdown, total RNA next-generation sequencing (RNA-seq) Biochimie Medium 33675855
2022 RPL38 directly interacts with the m6A methyltransferase METTL3 in chondrocytes (verified by co-immunoprecipitation). RPL38 promotes METTL3-mediated m6A modification of SOCS2 mRNA, suppressing SOCS2 expression. RPL38 knockdown de-represses SOCS2, which inhibits the JAK2/STAT3 proinflammatory pathway, reducing IL-1β-induced chondrocyte apoptosis, inflammatory cytokine secretion, and ECM degradation. In vivo RPL38 knockdown alleviated cartilage damage in OA mice. This defines a non-ribosomal role of RPL38 as a regulator of epitranscriptomic modification. Co-immunoprecipitation, siRNA knockdown, Western blot, flow cytometry (apoptosis), ELISA (cytokines), in vivo OA mouse model Inflammation research Medium 35596790
2024 In Drosophila testes, RpL38 depletion in spermatogonia blocked their transition to spermatocytes, causing male infertility. Proteomic analysis showed that RpL38-knockdown spermatogonia expressed spermatocyte markers but lacked meiosis-related proteins. Mechanistically, RpL38 depletion inhibited expression of bag of marbles (bam) at both mRNA and protein levels. bam loss phenocopied RpL38 RNAi, and bam overexpression fully rescued testis abnormality and infertility in RpL38-knockdown flies, establishing bam as the key downstream effector of RpL38 in spermatogonial differentiation. RNAi knockdown, proteomic analysis, transcriptomic profiling, genetic epistasis (bam overexpression rescue), immunostaining Science China. Life sciences High 39187660
2025 TurboID-based proximity labeling in Saccharomyces cerevisiae revealed that the importin Kap121/Pse1 is in close physical proximity to Rpl38 (eL38), suggesting that Kap121/Pse1 mediates nuclear import of Rpl38 prior to its assembly into pre-60S ribosomal particles. TurboID proximity labeling (BioID), mass spectrometry bioRxivpreprint Low

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
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
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2011 Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. Nature cell biology 490 21423176
2013 Structures of the human and Drosophila 80S ribosome. Nature 481 23636399
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
2004 The molecular mechanics of eukaryotic translation. Annual review of biochemistry 396 15189156
2015 Structure of the human 80S ribosome. Nature 380 25901680
2010 Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nature neuroscience 370 21170055
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2009 Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell 281 19167051
2003 Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control. Cell 276 14567916
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
1995 Structure and evolution of mammalian ribosomal proteins. Biochemistry and cell biology = Biochimie et biologie cellulaire 265 8722009
2022 Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 256 35063084
2017 Optimized fragmentation schemes and data analysis strategies for proteome-wide cross-link identification. Nature communications 221 28524877
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2009 Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Science signaling 207 19738201
2010 Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 195 20434207
2007 14-3-3sigma controls mitotic translation to facilitate cytokinesis. Nature 173 17361185
1978 Isolation of eukaryotic ribosomal proteins. Purification and characterization of the 60 S ribosomal subunit proteins La, Lb, Lf, P1, P2, L13', L14, L18', L20, and L38. The Journal of biological chemistry 112 621213
2004 Genetic analysis of RpL38 and RpL5, two minute genes located in the centric heterochromatin of chromosome 2 of Drosophila melanogaster. Genetics 55 15520262
2019 Biodegradation and metabolic fate of thiamphenicol via Chlorella sp. UTEX1602 and L38. Bioresource technology 34 31678704
2005 RPL38, FOSL1, and UPP1 are predominantly expressed in the pancreatic ductal epithelium. Pancreas 31 15714138
2022 RPL38 knockdown inhibits the inflammation and apoptosis in chondrocytes through regulating METTL3-mediated SOCS2 m6A modification in osteoarthritis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 30 35596790
2010 Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse. The Journal of biological chemistry 25 21062742
2022 Metabolic Mechanism of Sulfadimethoxine Biodegradation by Chlorella sp. L38 and Phaeodactylum tricornutum MASCC-0025. Frontiers in microbiology 13 35369425
1997 Primary sequence of the human, lysine-rich, ribosomal protein RPL38 and detection of an unusual RPL38 processed pseudogene in the promoter region of the type-1 angiotensin II receptor gene. Biochimica et biophysica acta 12 9375793
1991 The primary structure of rat ribosomal protein L38. Biochemical and biophysical research communications 12 1840484
2020 RPL38 Regulates the Proliferation and Apoptosis of Gastric Cancer via miR-374b-5p/VEGF Signal Pathway. OncoTargets and therapy 8 32617008
2024 RpL38 modulates germ cell differentiation by controlling Bam expression in Drosophila testis. Science China. Life sciences 6 39187660
2021 Knockdown of the mRNA encoding the ribosomal protein eL38 in mammalian cells causes a substantial reorganization of genomic transcription. Biochimie 5 33675855
2021 Knockdown of the Ribosomal Protein eL38 in HEK293 Cells Changes the Translational Efficiency of Specific Genes. International journal of molecular sciences 5 33926116
2020 Nitrite removal with potential value-added ingredients accumulation via Chlorella sp. L38. Bioresource technology 5 32620368
2022 RPL38 Regulates the Proliferation and Apoptosis of Gastric Cancer via miR-374b-5p/VEGF Signal Pathway [Retraction]. OncoTargets and therapy 1 36003326
2026 Decoding the role of RPL38 in lung adenocarcinoma: a multi-omics approach. Frontiers in immunology 0 41766901