Affinage

RPL39

Large ribosomal subunit protein eL39 · UniProt P62891

Length
51 aa
Mass
6.4 kDa
Annotated
2026-06-10
23 papers in source corpus 13 papers cited in narrative 13 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

RPL39 (eL39) is a small protein of the 60S large ribosomal subunit that lines the exit region of the nascent polypeptide exit tunnel and supports both the fidelity and the maturation of translating ribosomes (PMID:6706949, PMID:1002715, PMID:24072706). UV cross-linking places a domain of RPL39 at the tunnel exit, where it directly contacts both hydrophobic signal-anchor and hydrophilic segments of nascent chains (PMID:24072706), and its loss in yeast increases translational error frequency ~4-fold with elevated A-site binding, establishing it as a 60S protein required for translational accuracy (PMID:10852723). During 60S biogenesis RPL39 acts at middle nucleolar assembly stages, where its absence delays 27S and 7S pre-rRNA processing and perturbs rotation of the 5S RNP through long-range rRNA interactions, and it is needed for proper construction of the exit tunnel and correct co-translational protein folding (PMID:35639884). Loss of RPL39 reduces nascent protein synthesis and cell proliferation and alters mitochondrial function; these defects are rescued by RPL39, by an alanine-mutant of RPL39, or by the testis-enriched paralog RPL39L, which can substitute into ribosomes, indicating functional redundancy between the paralogs (PMID:34428590, PMID:20063902, PMID:12359333). Beyond its core ribosomal role, RPL39 has been linked in cancer contexts to nitric oxide synthase signaling via ADAR1-driven RNA editing and a recurrent A14V gain-of-function mutation (PMID:28040796, PMID:24876273), and to a mitochondrial physical interaction with acylglycerol kinase (AGK) affecting cristae morphology and ROS (PMID:35934718).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1984 High

    Before any functional role was known, the identity and covalent structure of L39 had to be defined; sequencing established it as a small, discrete 60S subunit protein.

    Evidence Tryptic peptide sequencing and Edman degradation of rat liver L39, building on its prior isolation as a 60S component

    PMID:1002715 PMID:6706949

    Open questions at the time
    • Primary structure alone gives no functional or positional information within the ribosome
    • No mammalian functional assay at this stage
  2. 2000 High

    It was unknown whether any 60S protein contributed to decoding fidelity; yeast genetics showed L39 loss raises translational error and A-site binding, making it the first large-subunit protein implicated in accuracy.

    Evidence Genetic deletion/point mutation in S. cerevisiae with polyphenylalanine synthesis and A/P-site binding assays

    PMID:10852723

    Open questions at the time
    • Did not localize the protein within the ribosome structurally
    • Mechanism linking a 60S protein to A-site (small-subunit) decoding left unresolved
  3. 2013 High

    The basis for L39's influence on translation was clarified by showing it physically occupies the exit tunnel and contacts nascent chains directly.

    Evidence UV cross-linking of ribosome-bound nascent chains with anti-Rpl39 immunoprecipitation in a homologous yeast system

    PMID:24072706

    Open questions at the time
    • Functional consequence of these contacts for folding not directly tested here
    • Whether tunnel contacts explain the fidelity defect not addressed
  4. 2022 High

    It was unclear when RPL39 acts in ribosome maturation; cryo-EM and pre-rRNA assays placed it at middle nucleolar assembly stages building the exit tunnel and tuning 5S RNP rotation, linking assembly to co-translational folding.

    Evidence Cryo-EM, pre-rRNA processing assays, assembly-intermediate fractionation, and protein folding assays

    PMID:35639884

    Open questions at the time
    • RPL39 not resolved by cryo-EM in early intermediates, so its early binding geometry is undefined
    • Direct mechanistic chain from assembly defect to misfolding not fully traced
  5. 2010 Medium

    Whether RPL39 function could be supplied by an alternative protein was addressed by identifying a testis-specific paralog (RPL39L) that incorporates into ribosomes via the nucleolus.

    Evidence 2D gel, mass spectrometry, RT-PCR and immunofluorescence on rodent testis ribosomes; complemented by a human RPL39-like gene study showing nucleolar/ribosome association

    PMID:12359333 PMID:20063902

    Open questions at the time
    • Did not test functional equivalence of paralog in translation
    • Physiological role of tissue-specific paralog substitution unknown
  6. 2021 Medium

    The cellular requirement for RPL39 and the degree of paralog redundancy were quantified, showing loss reduces nascent synthesis and proliferation with paralog cross-compensation.

    Evidence CRISPR/Cas9 single and double deletion of Rpl39/Rpl39l in mouse cells with nascent synthesis, proliferation, mitochondrial and rescue assays

    PMID:34428590

    Open questions at the time
    • Mechanism of compensatory Rpl39 upregulation unknown
    • Why an alanine mutant rescues as well as wild type not explained mechanistically
  7. 2022 Medium

    A non-canonical mitochondrial interaction was identified, linking RPL39 to AGK and mitochondrial physiology.

    Evidence Co-immunoprecipitation and proximity labeling plus EM and ROS assays in ovarian cancer cells

    PMID:35934718

    Open questions at the time
    • Whether interaction is ribosome-dependent or moonlighting not established
    • Direct molecular consequence of binding for AGK or RPL39 unresolved
  8. 2016 Medium

    In cancer, RPL39's pro-tumorigenic activity was connected to a defined signaling axis through iNOS and ADAR1-driven RNA editing, with a recurrent gain-of-function mutation.

    Evidence Co-immunoprecipitation, immunoblot, siRNA, patient-derived xenografts and digital PCR; building on earlier RPL39/MLF2-NOS work

    PMID:24876273 PMID:28040796

    Open questions at the time
    • How a ribosomal protein engages iNOS/ADAR1 mechanistically is unclear
    • Whether the A14V effect is ribosome-mediated or independent not resolved
  9. 2021 Medium

    A context-specific role outside translation control was reported, with RPL39 suppressing E-cadherin to promote trophoblast invasion.

    Evidence siRNA knockdown with cell cycle, migration/invasion, explant outgrowth and E-cadherin western blot in trophoblast cells

    PMID:33710681

    Open questions at the time
    • Mechanism linking RPL39 to E-cadherin regulation undefined
    • Single-cell-type observation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RPL39's structural position in the exit tunnel mechanistically connects its roles in decoding fidelity, co-translational folding, and the reported extra-ribosomal cancer/mitochondrial activities remains unresolved.
  • No structure of RPL39 in early assembly intermediates
  • No mechanistic account of how a tunnel-exit protein affects A-site fidelity
  • Unclear whether mitochondrial/iNOS roles are ribosome-dependent or moonlighting

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0003723 RNA binding 1
Localization
GO:0005730 nucleolus 3 GO:0005840 ribosome 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-8953854 Metabolism of RNA 1
Partners
ADAR1AGKMLF2
Complex memberships
60S large ribosomal subunit

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Yeast ribosomal protein L39 (Rpl39) is required for translational accuracy in Saccharomyces cerevisiae; deletion or mutation of L39 caused a 4-fold increase in error frequency, increased A-site binding (typical of error-prone mutants), sensitivity to paromomycin, decreased ribosomal subunit ratio, and cold-sensitive phenotype, establishing L39 as the first 60S ribosomal subunit protein implicated in translational accuracy. Genetic deletion and point mutation (spb2) in yeast, polyphenylalanine synthesis assay, A-site and P-site binding assays, antibiotic sensitivity assay Biochemistry High 10852723
2013 Yeast Rpl39 (the eukaryotic ortholog of RPL39) exposes a domain to the interior of the ribosomal exit tunnel and directly contacts nascent polypeptide chains. UV cross-linking established that Rpl39 contacts both hydrophobic signal anchor segments and hydrophilic segments, and its contacts are localized to the exit region of the tunnel. Rpl17 contacts were found in the middle region while Rpl4 contacts spanned throughout the tunnel. UV cross-linking of ribosome-bound nascent chains in homologous yeast translation system, antibody-based immunoprecipitation with anti-Rpl39 and anti-Rpl17 antibodies, His6-tagged Rpl4 pulldown, FLAG exposure assay The Journal of biological chemistry High 24072706
2022 Eukaryotic ribosomal protein eL39 (RPL39) is required for proper construction of the nascent polypeptide exit tunnel (NPET), maturation of pre-60S particles, and correct protein folding during translation. eL39 participates in pre-60S assembly during middle nucleolar stages (consistent with a delay in 27S and 7S pre-rRNA processing), is present in assembly intermediates even before being fully structurally accommodated (not resolved by cryo-EM in those particles), and influences rotation of the 5S ribonucleoprotein complex through long-range rRNA interactions. Cryo-electron microscopy, biochemical pre-rRNA processing assays, ribosome assembly intermediate fractionation, protein folding assays during translation Nucleic acids research High 35639884
1984 Rat liver ribosomal protein L39 is a 50-amino-acid protein (MW 7308) residing in the 60S ribosomal subunit; its complete primary structure was determined by tryptic peptide sequencing and Edman degradation. A portion of rat L39 sequence was found to be related to a fragment of E. coli ribosomal protein S1. Tryptic peptide purification, micromanual Edman degradation sequencing, cyanogen bromide cleavage, carboxypeptidase A treatment The Journal of biological chemistry High 6706949
1976 Rat liver ribosomal protein L39 was isolated as a component of the large (60S) ribosomal subunit. Its molecular weight was estimated by SDS-PAGE and amino acid composition was determined, with no detectable contamination. Ion exchange chromatography (carboxymethylcellulose), Sephadex gel filtration, SDS-PAGE molecular weight estimation, amino acid composition analysis The Journal of biological chemistry Medium 1002715
2010 A paralog of ribosomal protein L39, termed L39-like (RPL39L), was identified as a component of ribosomes specifically from rodent testis. Reverse transcription-PCR confirmed testis-specific expression, and immunofluorescence microscopy indicated that newly synthesized L39-like is transported to the nucleolus and then incorporated into translating cytoplasmic ribosomes, indicating that RPL39 paralogs can substitute into ribosomes in a tissue-specific manner. Two-dimensional gel electrophoresis, mass spectrometry, RT-PCR, immunofluorescence microscopy, polyacrylamide-agarose composite gel electrophoresis Journal of proteome research Medium 20063902
2002 A human gene (RPL39-like/L39-2) encoding a protein 92% identical to RPL39 is specifically expressed in normal testis but derepressed in cancer cells. When expressed in cells, the translated product localizes to the nucleus (strongly in the nucleolus) and cytoplasm by immunofluorescence, and associates with the large subunit of cytoplasmic ribosomes as detected by polyacrylamide-agarose composite gel electrophoresis followed by immunodetection. Immunofluorescence microscopy, polyacrylamide-agarose composite gel electrophoresis with immunodetection, mRNA expression analysis across tissues Biochimica et biophysica acta Medium 12359333
2021 CRISPR/Cas9 deletion of Rpl39 in mouse cells caused decreased cell proliferation, reduced nascent protein synthesis, and altered mitochondrial function. Double deletion of Rpl39 and its paralog Rpl39l augmented these phenotypes. Overexpression of Rpl39, Rpl39l, or an alanine mutant of RPL39 equally rescued cell proliferation in dual-null cells. Deletion of Rpl39l induced compensatory upregulation of Rpl39. CRISPR/Cas9 gene deletion, nascent protein synthesis assay, cell proliferation assay, mitochondrial function assays, overexpression rescue experiments The international journal of biochemistry & cell biology Medium 34428590
2014 RPL39 knockdown in breast cancer cells by shRNA/siRNA reduced tumor-initiating cell (breast cancer stem cell) self-renewal, tumor volume, and lung metastases in patient-derived xenografts. Both RPL39 and its partner MLF2 affect the nitric oxide synthase (NOS) pathway, and their activity is regulated by hypoxia. RNA deep sequencing identified damaging mutations in RPL39 in patient lung metastases. shRNA/siRNA knockdown, patient-derived xenograft models, RNA deep sequencing, BCSC self-renewal assays Proceedings of the National Academy of Sciences of the United States of America Medium 24876273
2016 In metaplastic breast cancer, RPL39 mediates its cancer-promoting actions through iNOS (inducible nitric oxide synthase) signaling driven by the RNA editing enzyme ADAR1 (adenosine deaminase acting on RNA 1). Co-immunoprecipitation and immunoblot analyses established this mechanistic link. The RPL39 A14V gain-of-function mutation was found at 97.5% rate in metaplastic breast cancer tumor samples. Co-immunoprecipitation, immunoblot, siRNA knockdown, patient-derived xenograft models, digital PCR for mutation detection Journal of the National Cancer Institute Medium 28040796
2021 RPL39 knockdown in trophoblast cells (Bewo and HTR8/SVneo) inhibited cell proliferation, migration, invasion, and placental explant outgrowth, caused G0/G1 cell cycle arrest, and increased expression of E-cadherin, indicating that RPL39 regulates trophoblast invasion by suppressing E-cadherin expression. siRNA knockdown, flow cytometry (cell cycle analysis), migration/invasion assays, placental explant outgrowth assay, western blot for E-cadherin FASEB journal Medium 33710681
2022 Acylglycerol kinase (AGK) physically interacts with RPL39 in mitochondria, as demonstrated by biotin identification (proximity labeling) and co-immunoprecipitation. This AGK-RPL39 interaction influences mitochondrial cristae morphogenesis and reactive oxygen species production in ovarian cancer cells. Co-immunoprecipitation, biotin identification (proximity labeling), transmission electron microscopy, microarray, flow cytometry Journal of experimental & clinical cancer research Medium 35934718
2014 RPL39 siRNA knockdown in pancreatic cancer cells (PANC-1 and BxPC-3) suppressed cell proliferation, induced apoptosis via increased caspase-8 activity and loss of mitochondrial membrane potential, and inhibited xenograft tumor growth in vivo, suggesting RPL39 is involved in caspase-8-related mitochondrial apoptosis pathway. siRNA knockdown, caspase-8 activity assay, mitochondrial membrane potential assay, xenograft tumor growth assay, Ki-67/CD31 immunostaining Biotechnology journal Low 24799381

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Yeast ribosomal protein L24 affects the kinetics of protein synthesis and ribosomal protein L39 improves translational accuracy, while mutants lacking both remain viable. Biochemistry 97 10852723
2014 Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. Proceedings of the National Academy of Sciences of the United States of America 94 24876273
1976 Isolation of eukaryotic ribosomal proteins. Purification and characterization of the 60 S ribosomal subunit proteins L4, L5, L7, L9, L11, L12, L13, L21, L22, L23, L26, L27, L30, L33, L35', L37, and L39. The Journal of biological chemistry 70 1002715
2016 Role of RPL39 in Metaplastic Breast Cancer. Journal of the National Cancer Institute 65 28040796
2010 Proteomic analysis of rodent ribosomes revealed heterogeneity including ribosomal proteins L10-like, L22-like 1, and L39-like. Journal of proteome research 60 20063902
2013 Interaction of nascent chains with the ribosomal tunnel proteins Rpl4, Rpl17, and Rpl39 of Saccharomyces cerevisiae. The Journal of biological chemistry 30 24072706
2006 Cloning and overexpression of ribosomal protein L39 gene from deltamethrin-resistant Culex pipiens pallens. Experimental parasitology 26 17092499
2002 A human gene encoding a protein homologous to ribosomal protein L39 is normally expressed in the testis and derepressed in multiple cancer cells. Biochimica et biophysica acta 26 12359333
1984 The primary structure of rat liver ribosomal protein L39. The Journal of biological chemistry 25 6706949
2000 Anti-tumour effects and pharmacokinetic profile of 17-(5'-isoxazolyl)androsta-4,16-dien-3-one (L-39) in mice: an inhibitor of androgen synthesis. British journal of cancer 22 10883671
2021 Downregulated ribosomal protein L39 inhibits trophoblast cell migration and invasion by targeting E-cadherin in the placenta of patients with preeclampsia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 33710681
2014 Knockdown of ribosomal protein L39 by RNA interference inhibits the growth of human pancreatic cancer cells in vitro and in vivo. Biotechnology journal 16 24799381
2022 Ribosomal protein eL39 is important for maturation of the nascent polypeptide exit tunnel and proper protein folding during translation. Nucleic acids research 12 35639884
2021 Deletion of ribosomal paralogs Rpl39 and Rpl39l compromises cell proliferation via protein synthesis and mitochondrial activity. The international journal of biochemistry & cell biology 11 34428590
1996 Primary structures and sequence analysis of human ribosomal proteins L39 and S27. Biochemistry and molecular biology international 10 8908372
2014 Effects of ribosomal protein l39-L on the drug resistance mechanisms of lung cancer A549 cells. Asian Pacific journal of cancer prevention : APJCP 9 24815453
2022 Acylglycerol kinase promotes ovarian cancer progression and regulates mitochondria function by interacting with ribosomal protein L39. Journal of experimental & clinical cancer research : CR 8 35934718
2014 Influence of ribosomal protein L39-L in the drug resistance mechanisms of lacrimal gland adenoid cystic carcinoma cells. Asian Pacific journal of cancer prevention : APJCP 7 24998577
1996 Molecular cloning of a cDNA encoding human ribosomal protein L39. Biochimica et biophysica acta 4 8764829
1995 The primary structures of rat ribosomal proteins: the characterization of the cDNAs for S21 and L39, corrections in the sequences of L7 and L18a, and the identification of L33. Biochemical and biophysical research communications 4 7654221
1997 Characterization and regulation of the genes encoding ribosomal proteins L39 and S7 of the human pathogen Candida albicans. Yeast (Chichester, England) 3 9364745
2025 RPL39 Was Associated With Sex Differences in Pulmonary Arterial Hypertension. Canadian respiratory journal 2 39957991
2026 Novel antimicrobial peptides derived from ribosomal protein L39 of large yellow croaker (Larimichthys crocea): promising therapeutic agents for controlling bacterial infections in aquaculture. Fish & shellfish immunology 0 41903591

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