{"gene":"RPL18","run_date":"2026-06-10T07:46:26","timeline":{"discoveries":[{"year":1999,"finding":"RPL18 (L18) binds to PKR and competes with dsRNA for binding to PKR's first dsRNA binding domain (K64 region), inhibiting both PKR autophosphorylation and PKR-mediated phosphorylation of eIF-2alpha in vitro. Overexpression of L18 reduced eIF-2alpha phosphorylation and stimulated translation in vivo.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (K64E), transient transfection with reporter gene","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus in vivo translation assay, single lab with multiple orthogonal methods","pmids":["9891046"],"is_preprint":false},{"year":2011,"finding":"Mitochondrial ribosomal protein L18 (MRPL18) acts as an import factor that, together with rhodanese, forms a molecular conveyor to redirect cytosolic 5S rRNA into mitochondria, where it associates with mitochondrial ribosomes.","method":"Biochemical fractionation, co-immunoprecipitation, RNA import assays, mitochondrial ribosome association assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, Co-IP, RNA import assay) in a single rigorous study","pmids":["21685364"],"is_preprint":false},{"year":2015,"finding":"MRPL18 contains a downstream CUG start codon and generates a cytosolic isoform in a stress-dependent manner; this cytosolic MRPL18 incorporates into the 80S ribosome and facilitates ribosome engagement on stress-selected mRNAs (HSPs), with knockdown substantially dampening cytosolic HSP expression at the translational level.","method":"Reporter assays, polysome profiling, ribosome fractionation, siRNA knockdown, metabolic labeling","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (polysome profiling, fractionation, knockdown with specific phenotype) in a single rigorous study","pmids":["25866880"],"is_preprint":false},{"year":2015,"finding":"RPL18 interacts with dengue virus NS1 protein and is redistributed to the perinuclear region after 48 h post-infection; silencing RPL18 reduces viral translation, replication, and viral yield without affecting overall cell translation efficiency or viability.","method":"Affinity chromatography, immunoprecipitation, siRNA knockdown, immunofluorescence, viral yield assay","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus siRNA knockdown with specific viral phenotype, single lab","pmids":["26092250"],"is_preprint":false},{"year":2020,"finding":"Rpl18 deficiency in zebrafish (CRISPR/Cas9 knockout) causes erythroid maturation defects mirroring Diamond-Blackfan anemia, with increased p53 activation and elevated JAK2-STAT3 activity; pharmacologic inhibition of JAK2 or STAT3 rescues anemia in rpl18 mutants.","method":"CRISPR/Cas9 knockout in zebrafish, pharmacologic inhibition (JAK2/STAT3 inhibitors), erythroid differentiation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific cellular phenotype and pathway rescue, single lab","pmids":["32075953"],"is_preprint":false},{"year":2017,"finding":"Chicken RPL18 interacts with IBDV VP3 and chicken PKR (chPKR) in host cells; knockdown of chRPL18 by RNAi promotes type I interferon expression and inhibits IBDV replication, indicating chRPL18 modulates antiviral signaling in association with VP3 and chPKR.","method":"Co-immunoprecipitation, RNAi knockdown, interferon expression assay, viral replication assay","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and RNAi with specific phenotype, single lab, multiple methods","pmids":["29273342"],"is_preprint":false},{"year":2025,"finding":"RPL18 stabilizes BTF3 mRNA, leading to increased BTF3 expression and activation of STAT3 signaling in melanoma cells, promoting proliferation, migration, and temozolomide resistance; RPL18-driven STAT3 activation also increases TGF-β secretion and induces M2 macrophage polarization. Pharmacologic STAT3 inhibition suppresses these phenotypes.","method":"Melanoma cell lines, patient-derived organoids, xenograft models, mRNA stability assays, pharmacologic STAT3 inhibition","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (cell lines, organoids, xenografts) with mechanistic follow-up, single lab","pmids":["41550725"],"is_preprint":false},{"year":1984,"finding":"E. coli ribosomal protein L18 binds 5S rRNA at specific sites; alpha-sarcin nuclease protection confirmed the binding site on 5S rRNA for L18 (and L25), establishing a direct RNA-protein interaction.","method":"Nuclease protection assay (alpha-sarcin ribonuclease), ribonucleoprotein complex analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — replicated across multiple studies using orthogonal nuclease methods","pmids":["6364140"],"is_preprint":false},{"year":1989,"finding":"Protein L18 binds primarily at the junctions of helix II and internal loops A and B in E. coli 5S RNA; L18 binding induces a conformational change in loop A that contributes to cooperative binding of L5 to helix I, and the basic N-terminal peptide of L18 interacts within the minor groove of helix I.","method":"Ribonuclease and chemical probing, site-directed mutagenesis of 5S RNA, circular dichroism","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with chemical/enzymatic probing and CD, replicated across labs","pmids":["2472486"],"is_preprint":false},{"year":1980,"finding":"The basic N-terminal region of L18 is accessible to trypsin in 5S RNA complexes, is not required for 5S RNA binding per se, but is essential for stimulating L5 binding and for 5S RNA–23S RNA complex formation; in 5S RNA–23S RNA complexes, L18 becomes strongly resistant to proteolysis.","method":"Limited trypsin digestion, ribosome reconstitution, RNA-protein and RNA-RNA complex assembly assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional proteolysis and reconstitution assays, single lab, multiple orthogonal methods","pmids":["6159586"],"is_preprint":false},{"year":1985,"finding":"Deletion of adenosine-66 from helix II of E. coli 5S RNA substantially weakens L18 binding, indicating that this unpaired nucleotide is a recognition site for L18; a tentative model proposes interaction between A66/G67 of RNA and glutamine-19 of L18.","method":"Site-directed mutagenesis (deletion of A66), protein-RNA binding assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with binding assay, single lab, single method","pmids":["2990903"],"is_preprint":false},{"year":1999,"finding":"Phosphorylation of a serine residue in Bacillus stearothermophilus L18 is required for proper protein folding and for 5S rRNA binding; dephosphorylated L18 does not bind 5S rRNA at neutral pH, and the dianionic phosphate stabilizes the native conformation, an effect modulated by Mg2+.","method":"Biochemical characterization of phosphoserine, Mg2+-dependent pKa measurement, RNA binding assay with dephosphorylated protein","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro biochemical assays with defined modification and binding readout, single lab","pmids":["10529214"],"is_preprint":false},{"year":2002,"finding":"The solution structure of Thermus thermophilus L18 revealed a mixed alpha/beta globular structure with a disordered N-terminal region; comparison with RNA-complexed L18 structures identified conserved RNA-recognition features including a bulge in the RNA-contacting beta-sheet, suggesting a conserved RNA-binding fold.","method":"NMR solution structure determination, structural comparison with known L18 structures","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure, single lab, no mutagenesis validation in this paper","pmids":["11964156"],"is_preprint":false},{"year":1978,"finding":"The minimal 5S RNA binding region of E. coli L18 spans approximately residues 18–117; the basic N-terminal region (residues 1–17) is not required for 5S RNA association but is accessible in the L18–5S RNA complex, suggesting it may mediate 5S RNA interaction with 23S RNA.","method":"Limited trypsin digestion of L18–5S RNA complex, 5S RNA binding assay with protein fragments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fragment analysis with functional binding readout, single lab","pmids":["353728"],"is_preprint":false},{"year":1977,"finding":"Protein L18 binding to 5S RNA induces a 20% increase in the 267 nm circular dichroism band (indicating increased secondary/possible tertiary structure of 5S RNA) and removes the pre-melting behavior in UV absorbance thermal denaturation, demonstrating that L18 stabilizes 5S RNA conformation.","method":"Circular dichroism spectroscopy, UV absorbance thermal denaturation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biophysical assays with defined structural readout, single lab, replicated in subsequent work","pmids":["333392"],"is_preprint":false},{"year":1981,"finding":"Iodination of tyrosine residue(s) in E. coli L18 abolishes 5S RNA binding activity; L18 pre-bound to 5S RNA is protected from iodination, indicating tyrosine is at or near the RNA binding interface.","method":"Chemical modification (iodination, tetranitromethane treatment), 5S RNA binding assay","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single chemical modification approach, single lab, indirect identification of binding residue","pmids":["7011398"],"is_preprint":false},{"year":2022,"finding":"RPL18 is upregulated in PEDV N protein-induced S-phase arrested cells and promotes PEDV replication; siRNA knockdown or overexpression of RPL18 respectively decreased or increased PEDV viral protein levels, indicating RPL18 promotes viral protein synthesis.","method":"Quantitative proteomics (TMT-labeling), siRNA knockdown, overexpression, viral replication assay","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomics plus functional knockdown/overexpression with specific viral phenotype, single lab","pmids":["36084747"],"is_preprint":false},{"year":2022,"finding":"Newcastle disease virus matrix (M) protein increases RPL18 expression in a dose-dependent manner; siRNA knockdown of RPL18 reduces NDV replication by decreasing viral protein translation (not viral RNA synthesis), while RPL18 overexpression enhances NDV replication.","method":"siRNA knockdown, overexpression, viral protein translation vs. RNA synthesis assays, plasmid transfection","journal":"Avian pathology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — knockdown and overexpression with specific mechanistic readout (translation vs. replication), single lab","pmids":["34859725"],"is_preprint":false}],"current_model":"RPL18 is a 60S large ribosomal subunit protein that directly binds 5S rRNA at helix II/internal loop junctions (requiring phosphorylation of a conserved serine for folding and binding), mediates 5S rRNA–23S rRNA assembly via its basic N-terminal region, negatively regulates PKR by competing with dsRNA for PKR's dsRNA-binding domain to suppress eIF-2alpha phosphorylation, generates a stress-inducible cytosolic isoform (from a downstream CUG codon) that incorporates into 80S ribosomes to facilitate translation of heat-shock mRNAs, and in its mitochondrial form (MRPL18) cooperates with rhodanese to import cytosolic 5S rRNA into mitochondria; additionally, RPL18 is co-opted by multiple viruses to promote viral translation and replication, and in cancer contexts activates a BTF3–STAT3 axis to drive proliferation, drug resistance, and immunosuppressive microenvironment remodeling."},"narrative":{"mechanistic_narrative":"RPL18 (bacterial L18) is a structural ribosomal protein whose core function is the recognition and conformational stabilization of 5S rRNA during large-subunit assembly [PMID:2472486, PMID:333392]. It binds 5S rRNA at the junctions of helix II and internal loops A and B, with an unpaired adenosine (A66) in helix II serving as a key recognition determinant [PMID:2472486, PMID:2990903]; binding induces a conformational change in loop A that licenses cooperative recruitment of L5 to helix I, and the basic N-terminal region — dispensable for 5S rRNA binding itself — is essential for stimulating L5 binding and for mediating 5S rRNA–23S rRNA complex assembly [PMID:2472486, PMID:6159586, PMID:353728]. The protein adopts a mixed alpha/beta globular fold with a disordered N-terminus and a conserved RNA-contacting beta-sheet bulge [PMID:11964156], and phosphorylation of a conserved serine stabilizes the native fold required for 5S rRNA binding [PMID:10529214]. Beyond its assembly role, RPL18 binds PKR and competes with double-stranded RNA for PKR's first dsRNA-binding domain, inhibiting PKR autophosphorylation and eIF-2alpha phosphorylation and thereby stimulating translation [PMID:9891046]. A stress-induced cytosolic isoform initiated from a downstream CUG codon incorporates into 80S ribosomes and promotes translation of heat-shock mRNAs, while a mitochondrial form acts with rhodanese to import cytosolic 5S rRNA into mitochondria [PMID:21685364, PMID:25866880]. RPL18 is repeatedly co-opted by viruses — dengue, IBDV, PEDV, and Newcastle disease virus — to support viral protein translation and replication [PMID:26092250, PMID:36084747, PMID:34859725], and in melanoma it stabilizes BTF3 mRNA to activate STAT3 signaling driving proliferation, drug resistance, and M2 macrophage polarization [PMID:41550725]. Loss of Rpl18 produces a Diamond-Blackfan-anemia-like erythroid maturation defect with p53 and JAK2-STAT3 activation [PMID:32075953].","teleology":[{"year":1977,"claim":"Establishing that L18 is not merely an inert subunit but actively reshapes its RNA target answered whether the protein contributes to 5S rRNA architecture.","evidence":"Circular dichroism and UV thermal denaturation of L18–5S RNA complexes in E. coli","pmids":["333392"],"confidence":"Medium","gaps":["Did not localize the structural change to specific RNA elements","No residue-level binding map"]},{"year":1980,"claim":"Dissecting which part of L18 does what separated the 5S-binding function from the assembly-bridging function, defining the basic N-terminus as an RNA-RNA coupling module.","evidence":"Limited trypsin digestion and reconstitution assays in E. coli (also residues 18–117 minimal binding region defined, #13)","pmids":["6159586","353728"],"confidence":"Medium","gaps":["Did not show direct N-terminus–23S RNA contact","Mechanism of L5 stimulation unresolved"]},{"year":1985,"claim":"Pinpointing A66 of helix II as a recognition site answered which 5S rRNA nucleotide L18 reads out.","evidence":"Site-directed deletion of A66 and binding assays in E. coli (binding-site mapping by alpha-sarcin protection, #7; iodination of tyrosine at the interface, #15)","pmids":["2990903","6364140","7011398"],"confidence":"Medium","gaps":["A66/Gln19 contact remained a model, not a structure","Tyrosine interface evidence rests on a single chemical-modification method"]},{"year":1989,"claim":"Showing that L18 binding remodels loop A to enable cooperative L5 recruitment established the protein as an ordered-assembly driver, not a passive binder.","evidence":"Ribonuclease/chemical probing, 5S RNA mutagenesis, and CD in E. coli","pmids":["2472486"],"confidence":"High","gaps":["No co-complex structure of L18–L5–5S RNA","Quantitative cooperativity parameters not defined"]},{"year":1999,"claim":"Identifying that serine phosphorylation is required for L18 folding and 5S rRNA binding answered how the binding-competent conformation is achieved.","evidence":"Phosphoserine biochemistry, Mg2+-dependent pKa measurement, and binding assay with dephosphorylated protein in B. stearothermophilus","pmids":["10529214"],"confidence":"Medium","gaps":["Responsible kinase/phosphatase not identified","Relevance to eukaryotic RPL18 not tested"]},{"year":1999,"claim":"The discovery that L18 binds and inhibits PKR revealed a moonlighting function in translational control distinct from ribosome assembly.","evidence":"Co-IP, in vitro kinase assays, K64E mutagenesis, and reporter translation assays","pmids":["9891046"],"confidence":"High","gaps":["Physiological conditions triggering PKR competition unclear","Stoichiometry of free vs ribosome-bound RPL18 unknown"]},{"year":2002,"claim":"The solution structure provided the fold underlying RNA recognition, identifying a conserved beta-sheet bulge as the RNA-contact surface.","evidence":"NMR structure of T. thermophilus L18 with comparison to RNA-bound structures","pmids":["11964156"],"confidence":"Medium","gaps":["No mutagenesis validation in this study","Disordered N-terminus not resolved structurally"]},{"year":2011,"claim":"Demonstrating that the mitochondrial form imports cytosolic 5S rRNA established an unexpected RNA-trafficking role for the protein.","evidence":"Biochemical fractionation, Co-IP, and RNA import assays with rhodanese","pmids":["21685364"],"confidence":"High","gaps":["Functional necessity of imported 5S rRNA inside mitochondria not fully defined","Import directionality determinants unclear"]},{"year":2015,"claim":"Finding a CUG-initiated cytosolic isoform that joins 80S ribosomes to translate heat-shock mRNAs revealed isoform-specific control of stress translation.","evidence":"Reporter assays, polysome profiling, ribosome fractionation, knockdown, and metabolic labeling","pmids":["25866880"],"confidence":"High","gaps":["Mechanism of mRNA selectivity for HSPs unresolved","How the isoform alters ribosome behavior not structurally defined"]},{"year":2020,"claim":"Linking Rpl18 loss to erythroid defects with p53 and JAK2-STAT3 activation connected the gene to ribosomopathy phenotypes.","evidence":"CRISPR/Cas9 knockout in zebrafish with pharmacologic JAK2/STAT3 rescue","pmids":["32075953"],"confidence":"Medium","gaps":["Human Diamond-Blackfan anemia causation by RPL18 not established here","How ribosome insufficiency triggers JAK2-STAT3 unclear"]},{"year":2022,"claim":"Multiple host-pathogen studies converged on RPL18 as a virus-exploited translation factor, answering whether viruses hijack it for protein synthesis specifically.","evidence":"siRNA knockdown/overexpression with translation-vs-replication readouts for PEDV and NDV (dengue NS1 interaction and redistribution, #3; IBDV VP3/chPKR interaction, #5)","pmids":["36084747","34859725","26092250","29273342"],"confidence":"Medium","gaps":["Whether viral exploitation uses the PKR-inhibitory or the ribosomal function is unresolved","Direct viral RNA–RPL18 contacts not mapped"]},{"year":2025,"claim":"The BTF3–STAT3 axis defined a pro-tumorigenic mRNA-stabilizing role for RPL18 in melanoma.","evidence":"Melanoma cell lines, patient-derived organoids, xenografts, mRNA stability assays, and STAT3 inhibition","pmids":["41550725"],"confidence":"Medium","gaps":["Mechanism by which RPL18 stabilizes BTF3 mRNA unknown","Whether this is ribosome-dependent or an extra-ribosomal activity unclear"]},{"year":null,"claim":"It remains unresolved whether RPL18's diverse extra-ribosomal activities (PKR inhibition, viral co-option, BTF3 stabilization, STAT3 activation) reflect a single biochemical property or distinct mechanisms of the same protein.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying structural or biochemical model linking ribosomal and moonlighting functions","Eukaryotic RPL18–5S rRNA contacts not directly mapped in human"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7,8,10,13,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[8,9,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[2,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,16,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5]}],"complexes":["60S/50S large ribosomal subunit","80S ribosome","mitochondrial ribosome","5S rRNA ribonucleoprotein"],"partners":["PKR","L5","5S RRNA","RHODANESE","BTF3","STAT3","DENGUE NS1","IBDV VP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q07020","full_name":"Large ribosomal subunit protein eL18","aliases":["60S ribosomal protein L18"],"length_aa":188,"mass_kda":21.6,"function":"Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25901680, PubMed:25957688, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:25901680, PubMed:25957688, PubMed:32669547)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm; Rough endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q07020/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL18","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":10.0},{"gene":"EIF2S3","stoichiometry":10.0},{"gene":"RACK1","stoichiometry":10.0},{"gene":"RBM8A","stoichiometry":10.0},{"gene":"RPL11","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL5","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"SRP72","stoichiometry":10.0},{"gene":"SRP9","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/RPL18","total_profiled":1310},"omim":[{"mim_id":"618310","title":"DIAMOND-BLACKFAN ANEMIA 18; DBA18","url":"https://www.omim.org/entry/618310"},{"mim_id":"604179","title":"RIBOSOMAL PROTEIN L18; RPL18","url":"https://www.omim.org/entry/604179"},{"mim_id":"105650","title":"DIAMOND-BLACKFAN ANEMIA 1; DBA1","url":"https://www.omim.org/entry/105650"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPL18"},"hgnc":{"alias_symbol":["L18","eL18"],"prev_symbol":[]},"alphafold":{"accession":"Q07020","domains":[{"cath_id":"3.100.10.10","chopping":"22-138","consensus_level":"high","plddt":96.6189,"start":22,"end":138},{"cath_id":"-","chopping":"146-188","consensus_level":"medium","plddt":94.343,"start":146,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07020","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q07020-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q07020-F1-predicted_aligned_error_v6.png","plddt_mean":95.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPL18","jax_strain_url":"https://www.jax.org/strain/search?query=RPL18"},"sequence":{"accession":"Q07020","fasta_url":"https://rest.uniprot.org/uniprotkb/Q07020.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q07020/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07020"}},"corpus_meta":[{"pmid":"621213","id":"PMC_621213","title":"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.","date":"1978","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/621213","citation_count":112,"is_preprint":false},{"pmid":"21685364","id":"PMC_21685364","title":"Biological significance of 5S rRNA import into human mitochondria: role of ribosomal protein MRP-L18.","date":"2011","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/21685364","citation_count":95,"is_preprint":false},{"pmid":"9891046","id":"PMC_9891046","title":"Double-stranded RNA-activated protein kinase (PKR) is negatively regulated by 60S ribosomal subunit protein L18.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9891046","citation_count":73,"is_preprint":false},{"pmid":"25866880","id":"PMC_25866880","title":"Translational control of the cytosolic stress response by mitochondrial ribosomal protein L18.","date":"2015","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25866880","citation_count":71,"is_preprint":false},{"pmid":"6364140","id":"PMC_6364140","title":"Nuclease protection analysis of ribonucleoprotein complexes: use of the cytotoxic ribonuclease alpha-sarcin to determine the binding sites for Escherichia coli ribosomal proteins L5, L18, and L25 on 5S rRNA.","date":"1984","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6364140","citation_count":69,"is_preprint":false},{"pmid":"863909","id":"PMC_863909","title":"Isolation of eukaryotic ribosomal proteins. Purification and characterization of 60 S ribosomal subunit proteins L3, L6, L7', L8, L10, L15, L17, L18, L19, L23', L25, L27', L28, L29, L31, L32, L34, L35, L36, L36', and L37'.","date":"1977","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/863909","citation_count":68,"is_preprint":false},{"pmid":"26092250","id":"PMC_26092250","title":"Dengue virus NS1 protein interacts with the ribosomal protein RPL18: this interaction is required for viral translation and replication in Huh-7 cells.","date":"2015","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/26092250","citation_count":67,"is_preprint":false},{"pmid":"379819","id":"PMC_379819","title":"A ribonuclease-resistant region of 5S RNA and its relation to the RNA binding sites of proteins L18 and L25.","date":"1979","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/379819","citation_count":66,"is_preprint":false},{"pmid":"142985","id":"PMC_142985","title":"Escherichia coli 5S RNA binding proteins L18 and L25 interact with 5.8S RNA but not with 5S RNA from yeast ribosomes.","date":"1977","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/142985","citation_count":54,"is_preprint":false},{"pmid":"22112725","id":"PMC_22112725","title":"Bioactive metabolites from Chaetomium globosum L18, an endophytic fungus in the medicinal plant Curcuma wenyujin.","date":"2011","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22112725","citation_count":45,"is_preprint":false},{"pmid":"827440","id":"PMC_827440","title":"RNA sequences associated with proteins L1, L9, and L5, L18, L25, in ribonucleoprotein fragments isolated from the 50-S subunit of Escherichia coli ribosomes.","date":"1976","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/827440","citation_count":42,"is_preprint":false},{"pmid":"333392","id":"PMC_333392","title":"Alteration of 5S RNA conformation by ribosomal proteins L18 and L25.","date":"1977","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/333392","citation_count":41,"is_preprint":false},{"pmid":"29374519","id":"PMC_29374519","title":"Ribosomal protein L18 is an essential factor that promote rice stripe virus accumulation in small brown planthopper.","date":"2018","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/29374519","citation_count":40,"is_preprint":false},{"pmid":"2990903","id":"PMC_2990903","title":"Does unpaired adenosine-66 from helix II of Escherichia coli 5S RNA bind to protein L18?","date":"1985","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2990903","citation_count":35,"is_preprint":false},{"pmid":"3318323","id":"PMC_3318323","title":"Augmentation of immune responses by a muramyl dipeptide analog, MDP-Lys(L18).","date":"1987","source":"Agents and actions","url":"https://pubmed.ncbi.nlm.nih.gov/3318323","citation_count":32,"is_preprint":false},{"pmid":"2472486","id":"PMC_2472486","title":"Protein L18 binds primarily at the junctions of helix II and internal loops A and B in Escherichia coli 5 S RNA. Implications for 5 S RNA structure.","date":"1989","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2472486","citation_count":31,"is_preprint":false},{"pmid":"6149171","id":"PMC_6149171","title":"Isolation and characterization of four mouse ribosomal-protein-L18 genes that appear to be processed pseudogenes.","date":"1984","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/6149171","citation_count":30,"is_preprint":false},{"pmid":"38087304","id":"PMC_38087304","title":"Beneficial effects of GABA-producing potential probiotic Limosilactobacillus fermentum L18 of human origin on intestinal permeability and human gut microbiota.","date":"2023","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/38087304","citation_count":24,"is_preprint":false},{"pmid":"3542562","id":"PMC_3542562","title":"The complete amino acid sequences of the 5 S rRNA binding proteins L5 and L18 from the moderate thermophile Bacillus stearothermophilus ribosome.","date":"1987","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/3542562","citation_count":24,"is_preprint":false},{"pmid":"353728","id":"PMC_353728","title":"Fragment of protein L18 from the Escherichia coli ribosome that contains the 5S RNA binding site.","date":"1978","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/353728","citation_count":23,"is_preprint":false},{"pmid":"6278442","id":"PMC_6278442","title":"Structural analyses of E. coli 5S RNA fragments, their associates and complexes with proteins L18 and L25.","date":"1982","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6278442","citation_count":21,"is_preprint":false},{"pmid":"21411292","id":"PMC_21411292","title":"A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18) and IFN-β synergistically induce dendritic cell maturation with augmented IL-12 production and suppress melanoma growth.","date":"2011","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/21411292","citation_count":20,"is_preprint":false},{"pmid":"6159586","id":"PMC_6159586","title":"The role of the basic N-terminal region of protein L18 in 5S RNA-23S RNA complex formation.","date":"1980","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6159586","citation_count":20,"is_preprint":false},{"pmid":"29273342","id":"PMC_29273342","title":"The association of ribosomal protein L18 (RPL18) with infectious bursal disease virus viral protein VP3 enhances viral replication.","date":"2017","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/29273342","citation_count":18,"is_preprint":false},{"pmid":"32075953","id":"PMC_32075953","title":"The nuclear gene rpl18 regulates erythroid maturation via JAK2-STAT3 signaling in zebrafish model of Diamond-Blackfan anemia.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32075953","citation_count":17,"is_preprint":false},{"pmid":"6773542","id":"PMC_6773542","title":"Purification of Drosophila ribosomal proteins. Isolation of proteins S8, S13, S14, S16, S19, S20/L24, S22/L26, S24, S25/S27, S26, S29, L4, L10/L11, L12, L13, L16, L18, L19, L27, 1, 7/8, 9, and 11.","date":"1980","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6773542","citation_count":16,"is_preprint":false},{"pmid":"3371159","id":"PMC_3371159","title":"The primary structure of rat ribosomal protein L18.","date":"1988","source":"DNA (Mary Ann Liebert, Inc.)","url":"https://pubmed.ncbi.nlm.nih.gov/3371159","citation_count":15,"is_preprint":false},{"pmid":"3060848","id":"PMC_3060848","title":"Exploration of the L18 binding site on 5S RNA by deletion mutagenesis.","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3060848","citation_count":13,"is_preprint":false},{"pmid":"11964156","id":"PMC_11964156","title":"The solution structure of ribosomal protein L18 from Thermus thermophilus reveals a conserved RNA-binding fold.","date":"2002","source":"The Biochemical 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biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/334548","citation_count":11,"is_preprint":false},{"pmid":"36084747","id":"PMC_36084747","title":"Up-regulated 60S ribosomal protein L18 in PEDV N protein-induced S-phase arrested host cells promotes viral replication.","date":"2022","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/36084747","citation_count":10,"is_preprint":false},{"pmid":"34859725","id":"PMC_34859725","title":"The association of ribosomal protein L18 with Newcastle disease virus matrix protein enhances viral translation and replication.","date":"2022","source":"Avian pathology : journal of the W.V.P.A","url":"https://pubmed.ncbi.nlm.nih.gov/34859725","citation_count":9,"is_preprint":false},{"pmid":"34370148","id":"PMC_34370148","title":"Characterization of β-glucosidase of Lactobacillus plantarum FSO1 and Candida pelliculosa L18 isolated from traditional fermented green olive.","date":"2021","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34370148","citation_count":8,"is_preprint":false},{"pmid":"10688489","id":"PMC_10688489","title":"Intrapleural therapy with MDP-Lys (L18), a synthetic derivative of muramyl dipeptide, against malignant pleurisy associated with lung cancer.","date":"2000","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/10688489","citation_count":8,"is_preprint":false},{"pmid":"39322125","id":"PMC_39322125","title":"Identification of the ribosomal protein L18 (RPL18) gene family reveals that TaRPL18-1 positively regulates powdery mildew resistance in wheat.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39322125","citation_count":7,"is_preprint":false},{"pmid":"30537602","id":"PMC_30537602","title":"Cre-miR914-regulated RPL18 is involved with UV-B adaptation in Chlamydomonas reinhardtii.","date":"2018","source":"Journal of plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30537602","citation_count":7,"is_preprint":false},{"pmid":"1568468","id":"PMC_1568468","title":"In vitro and in vivo effects of MDP-Lys(L18) on mouse megakaryocyte progenitor cells (CFU-Meg).","date":"1992","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/1568468","citation_count":7,"is_preprint":false},{"pmid":"14687565","id":"PMC_14687565","title":"The solution structure of ribosomal protein L18 from Bacillus stearothermophilus.","date":"2004","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14687565","citation_count":7,"is_preprint":false},{"pmid":"8996113","id":"PMC_8996113","title":"Sequence, overproduction and purification of Vibrio proteolyticus ribosomal protein L18 for in vitro and in vivo studies.","date":"1996","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8996113","citation_count":6,"is_preprint":false},{"pmid":"11524947","id":"PMC_11524947","title":"[The Thermus thermophilus 5S rRNA-protein complex: Identifications of specific binding sites for proteins L5 and L18 in 5S rRNA].","date":"2001","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/11524947","citation_count":6,"is_preprint":false},{"pmid":"8926048","id":"PMC_8926048","title":"Inflammatory cytokine production induced by an analogue of muramyl dipeptide MDP-Lys(L18) in rat macrophage cultures and dog synovial fluid.","date":"1996","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/8926048","citation_count":6,"is_preprint":false},{"pmid":"11566355","id":"PMC_11566355","title":"Gene structure and promoter function of a teleost ribosomal protein: a tilapia (Oreochromis mossambicus) L18 gene.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11566355","citation_count":5,"is_preprint":false},{"pmid":"37431269","id":"PMC_37431269","title":"Decreased expression of RPL15 and RPL18 exacerbated the calcification of valve interstitial cells during aortic valve calcification.","date":"2023","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/37431269","citation_count":4,"is_preprint":false},{"pmid":"35621103","id":"PMC_35621103","title":"[Prevalence, Diversity, and Evolution of L18 (DD37E) Transposons in the Genomes of Cnidarians].","date":"2022","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/35621103","citation_count":4,"is_preprint":false},{"pmid":"8950179","id":"PMC_8950179","title":"The cloning and sequencing of a ribosomal L18 protein from an evolutionary divergent eukaryote, Trypanosoma brucei.","date":"1996","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8950179","citation_count":4,"is_preprint":false},{"pmid":"8359697","id":"PMC_8359697","title":"Sequence analysis of mouse cDNAs encoding ribosomal proteins L12 and L18.","date":"1993","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8359697","citation_count":4,"is_preprint":false},{"pmid":"34121902","id":"PMC_34121902","title":"Molecular characterization and expression analysis of ribosomal L18/L5e gene in Pennisetum glaucum (L.) R. Br.","date":"2021","source":"Saudi journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34121902","citation_count":3,"is_preprint":false},{"pmid":"38770762","id":"PMC_38770762","title":"CD62-L down-regulation after L18-MDP stimulation as a complementary flow cytometry functional assay for the diagnosis of XIAP deficiency.","date":"2024","source":"Cytometry. Part B, Clinical cytometry","url":"https://pubmed.ncbi.nlm.nih.gov/38770762","citation_count":3,"is_preprint":false},{"pmid":"7011398","id":"PMC_7011398","title":"Iodination of Escherichia coli ribosomal protein L18 abolishes its 5 S RNA binding activity.","date":"1981","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7011398","citation_count":2,"is_preprint":false},{"pmid":"41550725","id":"PMC_41550725","title":"RPL18 promotes melanoma progression and drug resistance via BTF3/STAT3-dependent mechanisms and immune modulation.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41550725","citation_count":0,"is_preprint":false},{"pmid":"41794485","id":"PMC_41794485","title":"Integrated transcriptomic and metabolomic analyses reveal the antibacterial mechanism of whey fermentation powder against Bacillus cereus L18 and its efficacy in Liangpi preservation.","date":"2026","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/41794485","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.08.687394","title":"Virulence and genomic analysis of  <i>Puccinia coronata</i>  f. sp.  <i>avenae</i>  in Australia identifies new races and a new lineage in 2024","date":"2025-11-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.08.687394","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24438,"output_tokens":4019,"usd":0.066799,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11904,"output_tokens":4054,"usd":0.080435,"stage2_stop_reason":"end_turn"},"total_usd":0.147234,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"RPL18 (L18) binds to PKR and competes with dsRNA for binding to PKR's first dsRNA binding domain (K64 region), inhibiting both PKR autophosphorylation and PKR-mediated phosphorylation of eIF-2alpha in vitro. Overexpression of L18 reduced eIF-2alpha phosphorylation and stimulated translation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (K64E), transient transfection with reporter gene\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus in vivo translation assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9891046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mitochondrial ribosomal protein L18 (MRPL18) acts as an import factor that, together with rhodanese, forms a molecular conveyor to redirect cytosolic 5S rRNA into mitochondria, where it associates with mitochondrial ribosomes.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, RNA import assays, mitochondrial ribosome association assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, Co-IP, RNA import assay) in a single rigorous study\",\n      \"pmids\": [\"21685364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MRPL18 contains a downstream CUG start codon and generates a cytosolic isoform in a stress-dependent manner; this cytosolic MRPL18 incorporates into the 80S ribosome and facilitates ribosome engagement on stress-selected mRNAs (HSPs), with knockdown substantially dampening cytosolic HSP expression at the translational level.\",\n      \"method\": \"Reporter assays, polysome profiling, ribosome fractionation, siRNA knockdown, metabolic labeling\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (polysome profiling, fractionation, knockdown with specific phenotype) in a single rigorous study\",\n      \"pmids\": [\"25866880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPL18 interacts with dengue virus NS1 protein and is redistributed to the perinuclear region after 48 h post-infection; silencing RPL18 reduces viral translation, replication, and viral yield without affecting overall cell translation efficiency or viability.\",\n      \"method\": \"Affinity chromatography, immunoprecipitation, siRNA knockdown, immunofluorescence, viral yield assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus siRNA knockdown with specific viral phenotype, single lab\",\n      \"pmids\": [\"26092250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rpl18 deficiency in zebrafish (CRISPR/Cas9 knockout) causes erythroid maturation defects mirroring Diamond-Blackfan anemia, with increased p53 activation and elevated JAK2-STAT3 activity; pharmacologic inhibition of JAK2 or STAT3 rescues anemia in rpl18 mutants.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, pharmacologic inhibition (JAK2/STAT3 inhibitors), erythroid differentiation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific cellular phenotype and pathway rescue, single lab\",\n      \"pmids\": [\"32075953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Chicken RPL18 interacts with IBDV VP3 and chicken PKR (chPKR) in host cells; knockdown of chRPL18 by RNAi promotes type I interferon expression and inhibits IBDV replication, indicating chRPL18 modulates antiviral signaling in association with VP3 and chPKR.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, interferon expression assay, viral replication assay\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and RNAi with specific phenotype, single lab, multiple methods\",\n      \"pmids\": [\"29273342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPL18 stabilizes BTF3 mRNA, leading to increased BTF3 expression and activation of STAT3 signaling in melanoma cells, promoting proliferation, migration, and temozolomide resistance; RPL18-driven STAT3 activation also increases TGF-β secretion and induces M2 macrophage polarization. Pharmacologic STAT3 inhibition suppresses these phenotypes.\",\n      \"method\": \"Melanoma cell lines, patient-derived organoids, xenograft models, mRNA stability assays, pharmacologic STAT3 inhibition\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (cell lines, organoids, xenografts) with mechanistic follow-up, single lab\",\n      \"pmids\": [\"41550725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"E. coli ribosomal protein L18 binds 5S rRNA at specific sites; alpha-sarcin nuclease protection confirmed the binding site on 5S rRNA for L18 (and L25), establishing a direct RNA-protein interaction.\",\n      \"method\": \"Nuclease protection assay (alpha-sarcin ribonuclease), ribonucleoprotein complex analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple studies using orthogonal nuclease methods\",\n      \"pmids\": [\"6364140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Protein L18 binds primarily at the junctions of helix II and internal loops A and B in E. coli 5S RNA; L18 binding induces a conformational change in loop A that contributes to cooperative binding of L5 to helix I, and the basic N-terminal peptide of L18 interacts within the minor groove of helix I.\",\n      \"method\": \"Ribonuclease and chemical probing, site-directed mutagenesis of 5S RNA, circular dichroism\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with chemical/enzymatic probing and CD, replicated across labs\",\n      \"pmids\": [\"2472486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1980,\n      \"finding\": \"The basic N-terminal region of L18 is accessible to trypsin in 5S RNA complexes, is not required for 5S RNA binding per se, but is essential for stimulating L5 binding and for 5S RNA–23S RNA complex formation; in 5S RNA–23S RNA complexes, L18 becomes strongly resistant to proteolysis.\",\n      \"method\": \"Limited trypsin digestion, ribosome reconstitution, RNA-protein and RNA-RNA complex assembly assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional proteolysis and reconstitution assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"6159586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Deletion of adenosine-66 from helix II of E. coli 5S RNA substantially weakens L18 binding, indicating that this unpaired nucleotide is a recognition site for L18; a tentative model proposes interaction between A66/G67 of RNA and glutamine-19 of L18.\",\n      \"method\": \"Site-directed mutagenesis (deletion of A66), protein-RNA binding assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with binding assay, single lab, single method\",\n      \"pmids\": [\"2990903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Phosphorylation of a serine residue in Bacillus stearothermophilus L18 is required for proper protein folding and for 5S rRNA binding; dephosphorylated L18 does not bind 5S rRNA at neutral pH, and the dianionic phosphate stabilizes the native conformation, an effect modulated by Mg2+.\",\n      \"method\": \"Biochemical characterization of phosphoserine, Mg2+-dependent pKa measurement, RNA binding assay with dephosphorylated protein\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro biochemical assays with defined modification and binding readout, single lab\",\n      \"pmids\": [\"10529214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The solution structure of Thermus thermophilus L18 revealed a mixed alpha/beta globular structure with a disordered N-terminal region; comparison with RNA-complexed L18 structures identified conserved RNA-recognition features including a bulge in the RNA-contacting beta-sheet, suggesting a conserved RNA-binding fold.\",\n      \"method\": \"NMR solution structure determination, structural comparison with known L18 structures\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure, single lab, no mutagenesis validation in this paper\",\n      \"pmids\": [\"11964156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1978,\n      \"finding\": \"The minimal 5S RNA binding region of E. coli L18 spans approximately residues 18–117; the basic N-terminal region (residues 1–17) is not required for 5S RNA association but is accessible in the L18–5S RNA complex, suggesting it may mediate 5S RNA interaction with 23S RNA.\",\n      \"method\": \"Limited trypsin digestion of L18–5S RNA complex, 5S RNA binding assay with protein fragments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fragment analysis with functional binding readout, single lab\",\n      \"pmids\": [\"353728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1977,\n      \"finding\": \"Protein L18 binding to 5S RNA induces a 20% increase in the 267 nm circular dichroism band (indicating increased secondary/possible tertiary structure of 5S RNA) and removes the pre-melting behavior in UV absorbance thermal denaturation, demonstrating that L18 stabilizes 5S RNA conformation.\",\n      \"method\": \"Circular dichroism spectroscopy, UV absorbance thermal denaturation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biophysical assays with defined structural readout, single lab, replicated in subsequent work\",\n      \"pmids\": [\"333392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1981,\n      \"finding\": \"Iodination of tyrosine residue(s) in E. coli L18 abolishes 5S RNA binding activity; L18 pre-bound to 5S RNA is protected from iodination, indicating tyrosine is at or near the RNA binding interface.\",\n      \"method\": \"Chemical modification (iodination, tetranitromethane treatment), 5S RNA binding assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single chemical modification approach, single lab, indirect identification of binding residue\",\n      \"pmids\": [\"7011398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RPL18 is upregulated in PEDV N protein-induced S-phase arrested cells and promotes PEDV replication; siRNA knockdown or overexpression of RPL18 respectively decreased or increased PEDV viral protein levels, indicating RPL18 promotes viral protein synthesis.\",\n      \"method\": \"Quantitative proteomics (TMT-labeling), siRNA knockdown, overexpression, viral replication assay\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomics plus functional knockdown/overexpression with specific viral phenotype, single lab\",\n      \"pmids\": [\"36084747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Newcastle disease virus matrix (M) protein increases RPL18 expression in a dose-dependent manner; siRNA knockdown of RPL18 reduces NDV replication by decreasing viral protein translation (not viral RNA synthesis), while RPL18 overexpression enhances NDV replication.\",\n      \"method\": \"siRNA knockdown, overexpression, viral protein translation vs. RNA synthesis assays, plasmid transfection\",\n      \"journal\": \"Avian pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — knockdown and overexpression with specific mechanistic readout (translation vs. replication), single lab\",\n      \"pmids\": [\"34859725\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPL18 is a 60S large ribosomal subunit protein that directly binds 5S rRNA at helix II/internal loop junctions (requiring phosphorylation of a conserved serine for folding and binding), mediates 5S rRNA–23S rRNA assembly via its basic N-terminal region, negatively regulates PKR by competing with dsRNA for PKR's dsRNA-binding domain to suppress eIF-2alpha phosphorylation, generates a stress-inducible cytosolic isoform (from a downstream CUG codon) that incorporates into 80S ribosomes to facilitate translation of heat-shock mRNAs, and in its mitochondrial form (MRPL18) cooperates with rhodanese to import cytosolic 5S rRNA into mitochondria; additionally, RPL18 is co-opted by multiple viruses to promote viral translation and replication, and in cancer contexts activates a BTF3–STAT3 axis to drive proliferation, drug resistance, and immunosuppressive microenvironment remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL18 (bacterial L18) is a structural ribosomal protein whose core function is the recognition and conformational stabilization of 5S rRNA during large-subunit assembly [#8, #14]. It binds 5S rRNA at the junctions of helix II and internal loops A and B, with an unpaired adenosine (A66) in helix II serving as a key recognition determinant [#8, #10]; binding induces a conformational change in loop A that licenses cooperative recruitment of L5 to helix I, and the basic N-terminal region — dispensable for 5S rRNA binding itself — is essential for stimulating L5 binding and for mediating 5S rRNA–23S rRNA complex assembly [#8, #9, #13]. The protein adopts a mixed alpha/beta globular fold with a disordered N-terminus and a conserved RNA-contacting beta-sheet bulge [#12], and phosphorylation of a conserved serine stabilizes the native fold required for 5S rRNA binding [#11]. Beyond its assembly role, RPL18 binds PKR and competes with double-stranded RNA for PKR's first dsRNA-binding domain, inhibiting PKR autophosphorylation and eIF-2alpha phosphorylation and thereby stimulating translation [#0]. A stress-induced cytosolic isoform initiated from a downstream CUG codon incorporates into 80S ribosomes and promotes translation of heat-shock mRNAs, while a mitochondrial form acts with rhodanese to import cytosolic 5S rRNA into mitochondria [#1, #2]. RPL18 is repeatedly co-opted by viruses — dengue, IBDV, PEDV, and Newcastle disease virus — to support viral protein translation and replication [#3, #16, #17], and in melanoma it stabilizes BTF3 mRNA to activate STAT3 signaling driving proliferation, drug resistance, and M2 macrophage polarization [#6]. Loss of Rpl18 produces a Diamond-Blackfan-anemia-like erythroid maturation defect with p53 and JAK2-STAT3 activation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1977,\n      \"claim\": \"Establishing that L18 is not merely an inert subunit but actively reshapes its RNA target answered whether the protein contributes to 5S rRNA architecture.\",\n      \"evidence\": \"Circular dichroism and UV thermal denaturation of L18–5S RNA complexes in E. coli\",\n      \"pmids\": [\"333392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not localize the structural change to specific RNA elements\", \"No residue-level binding map\"]\n    },\n    {\n      \"year\": 1980,\n      \"claim\": \"Dissecting which part of L18 does what separated the 5S-binding function from the assembly-bridging function, defining the basic N-terminus as an RNA-RNA coupling module.\",\n      \"evidence\": \"Limited trypsin digestion and reconstitution assays in E. coli (also residues 18–117 minimal binding region defined, #13)\",\n      \"pmids\": [\"6159586\", \"353728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not show direct N-terminus–23S RNA contact\", \"Mechanism of L5 stimulation unresolved\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Pinpointing A66 of helix II as a recognition site answered which 5S rRNA nucleotide L18 reads out.\",\n      \"evidence\": \"Site-directed deletion of A66 and binding assays in E. coli (binding-site mapping by alpha-sarcin protection, #7; iodination of tyrosine at the interface, #15)\",\n      \"pmids\": [\"2990903\", \"6364140\", \"7011398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"A66/Gln19 contact remained a model, not a structure\", \"Tyrosine interface evidence rests on a single chemical-modification method\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Showing that L18 binding remodels loop A to enable cooperative L5 recruitment established the protein as an ordered-assembly driver, not a passive binder.\",\n      \"evidence\": \"Ribonuclease/chemical probing, 5S RNA mutagenesis, and CD in E. coli\",\n      \"pmids\": [\"2472486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-complex structure of L18–L5–5S RNA\", \"Quantitative cooperativity parameters not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying that serine phosphorylation is required for L18 folding and 5S rRNA binding answered how the binding-competent conformation is achieved.\",\n      \"evidence\": \"Phosphoserine biochemistry, Mg2+-dependent pKa measurement, and binding assay with dephosphorylated protein in B. stearothermophilus\",\n      \"pmids\": [\"10529214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible kinase/phosphatase not identified\", \"Relevance to eukaryotic RPL18 not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The discovery that L18 binds and inhibits PKR revealed a moonlighting function in translational control distinct from ribosome assembly.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, K64E mutagenesis, and reporter translation assays\",\n      \"pmids\": [\"9891046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions triggering PKR competition unclear\", \"Stoichiometry of free vs ribosome-bound RPL18 unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The solution structure provided the fold underlying RNA recognition, identifying a conserved beta-sheet bulge as the RNA-contact surface.\",\n      \"evidence\": \"NMR structure of T. thermophilus L18 with comparison to RNA-bound structures\",\n      \"pmids\": [\"11964156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation in this study\", \"Disordered N-terminus not resolved structurally\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that the mitochondrial form imports cytosolic 5S rRNA established an unexpected RNA-trafficking role for the protein.\",\n      \"evidence\": \"Biochemical fractionation, Co-IP, and RNA import assays with rhodanese\",\n      \"pmids\": [\"21685364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional necessity of imported 5S rRNA inside mitochondria not fully defined\", \"Import directionality determinants unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Finding a CUG-initiated cytosolic isoform that joins 80S ribosomes to translate heat-shock mRNAs revealed isoform-specific control of stress translation.\",\n      \"evidence\": \"Reporter assays, polysome profiling, ribosome fractionation, knockdown, and metabolic labeling\",\n      \"pmids\": [\"25866880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mRNA selectivity for HSPs unresolved\", \"How the isoform alters ribosome behavior not structurally defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking Rpl18 loss to erythroid defects with p53 and JAK2-STAT3 activation connected the gene to ribosomopathy phenotypes.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in zebrafish with pharmacologic JAK2/STAT3 rescue\",\n      \"pmids\": [\"32075953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human Diamond-Blackfan anemia causation by RPL18 not established here\", \"How ribosome insufficiency triggers JAK2-STAT3 unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple host-pathogen studies converged on RPL18 as a virus-exploited translation factor, answering whether viruses hijack it for protein synthesis specifically.\",\n      \"evidence\": \"siRNA knockdown/overexpression with translation-vs-replication readouts for PEDV and NDV (dengue NS1 interaction and redistribution, #3; IBDV VP3/chPKR interaction, #5)\",\n      \"pmids\": [\"36084747\", \"34859725\", \"26092250\", \"29273342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether viral exploitation uses the PKR-inhibitory or the ribosomal function is unresolved\", \"Direct viral RNA–RPL18 contacts not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The BTF3–STAT3 axis defined a pro-tumorigenic mRNA-stabilizing role for RPL18 in melanoma.\",\n      \"evidence\": \"Melanoma cell lines, patient-derived organoids, xenografts, mRNA stability assays, and STAT3 inhibition\",\n      \"pmids\": [\"41550725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RPL18 stabilizes BTF3 mRNA unknown\", \"Whether this is ribosome-dependent or an extra-ribosomal activity unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether RPL18's diverse extra-ribosomal activities (PKR inhibition, viral co-option, BTF3 stabilization, STAT3 activation) reflect a single biochemical property or distinct mechanisms of the same protein.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying structural or biochemical model linking ribosomal and moonlighting functions\", \"Eukaryotic RPL18–5S rRNA contacts not directly mapped in human\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7, 8, 10, 13, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [8, 9, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 16, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [\n      \"60S/50S large ribosomal subunit\",\n      \"80S ribosome\",\n      \"mitochondrial ribosome\",\n      \"5S rRNA ribonucleoprotein\"\n    ],\n    \"partners\": [\n      \"PKR\",\n      \"L5\",\n      \"5S rRNA\",\n      \"rhodanese\",\n      \"BTF3\",\n      \"STAT3\",\n      \"dengue NS1\",\n      \"IBDV VP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}