{"gene":"RPL23","run_date":"2026-06-10T07:46:26","timeline":{"discoveries":[{"year":2004,"finding":"RPL23 interacts with MDM2 (via immunoaffinity purification), forming a complex independent of the 80S ribosome and polysome. This interaction is enhanced by actinomycin D (ribosomal perturbation) but not gamma-irradiation. Ectopic L23 expression reduces MDM2-mediated p53 ubiquitination and induces p53 activity and G1 arrest in p53-proficient cells; siRNA knockdown of L23 abolishes this activation.","method":"Immunoaffinity purification, co-IP, siRNA knockdown, ubiquitination assay, flow cytometry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, loss-of-function siRNA, ubiquitination assay, replicated in companion paper same year","pmids":["15314173"],"is_preprint":false},{"year":2004,"finding":"RPL23 (L23) interacts with HDM2 through the central acidic domain of HDM2 and an N-terminal domain of L23. L23 and L11 can simultaneously yet distinctly bind HDM2, forming a ternary complex. Overexpressed L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes p53-dependent cell cycle arrest. Knockdown of L23 triggers nucleolar stress, translocation of B23 from nucleolus to nucleoplasm, and stabilization/activation of p53.","method":"Co-IP, domain-mapping experiments, p53 ubiquitination assay, siRNA knockdown, flow cytometry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-mapped co-IP, ubiquitination assay, loss-of-function knockdown, replicated by companion paper","pmids":["15314174"],"is_preprint":false},{"year":2002,"finding":"In E. coli, L23 (bacterial ortholog of RPL23/uL14) is located at the ribosomal peptide exit tunnel and serves as an essential docking site for the chaperone Trigger Factor. Mutation of an exposed glutamate in L23 prevents Trigger Factor from interacting with ribosomes and nascent chains, causes protein aggregation, and causes conditional lethality. Purified L23 interacts specifically with Trigger Factor in vitro.","method":"Crosslinking, in vitro binding assay, mutagenesis, genetic complementation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, site-directed mutagenesis, multiple orthogonal methods in one rigorous study","pmids":["12226666"],"is_preprint":false},{"year":2003,"finding":"The signal recognition particle (SRP) component Ffh crosslinks to ribosomal protein L23 at the peptide exit of the E. coli 50S subunit. Two positions in the N domain of Ffh crosslink predominantly to L23. Binding of a nascent signal peptide induces a slightly different arrangement of SRP on L23.","method":"Site-specific UV-induced crosslinking (p-azidophenacyl bromide), biochemical mapping","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific crosslinking with engineered cysteines, multiple positions tested, single lab","pmids":["12702815"],"is_preprint":false},{"year":2003,"finding":"Both Trigger Factor (TF) and SRP interact with the signal anchor sequence of nascent inner membrane proteins and contact L23 and L29 at the ribosomal exit site. TF and SRP compete for binding to L23 on non-translating ribosomes, with SRP having a competitive advantage.","method":"Photocrosslinking of nascent chains, in vitro binding assay with purified components","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — photocrosslinking with in vitro reconstitution, competitive binding assay, single lab","pmids":["12756233"],"is_preprint":false},{"year":2005,"finding":"The nascent polypeptide-associated complex (NAC) contacts L23 (ribosomal protein family member) at the ribosomal exit site via a conserved RRK(X)nKK ribosome-binding motif in the β-subunit of NAC. UV-crosslinking of the motif specifically crosslinks to L23 at the exit site. Mutations of L23 reduce NAC ribosome binding in vivo and in vitro without affecting other ribosome-associated factors (Ssb, Zuotin).","method":"UV-activatable crosslinking, mutagenesis of L23, in vivo and in vitro binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crosslinking with mutagenesis, both in vivo and in vitro validation, single lab","pmids":["16316984"],"is_preprint":false},{"year":2008,"finding":"RPL23 functions as a negative regulator of Miz1-dependent transactivation by retaining nucleophosmin (an essential co-activator of Miz1) in the nucleolus, thereby preventing Miz1-induced expression of cell-cycle inhibitors p15(Ink4b) and p21(Cip1). RPL23 is encoded by a direct Myc target gene, forming a feedback circuit linking translation/cell growth with Miz1-dependent cell-cycle arrest.","method":"Co-IP, nucleolar retention assay, reporter assays for Miz1 transactivation, knockdown experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, subcellular fractionation showing nucleolar retention, loss-of-function with defined molecular phenotype, single lab with multiple orthogonal methods","pmids":["19160485"],"is_preprint":false},{"year":2003,"finding":"NMR structure of ribosomal protein L23 from Thermus thermophilus determined in solution. Uncomplexed L23 has a well-ordered core (four anti-parallel beta-strands and three alpha-helices in a beta-alpha-beta-alpha-beta-beta-alpha topology) with a large flexible loop between strands 3 and 4. In RNA-complexed crystal structures, this flexible loop becomes rigid and forms part of the ribosomal exit tunnel wall through interactions with rRNA.","method":"NMR structure determination, comparison with crystal structures","journal":"Journal of biomolecular NMR","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional comparison to crystal structures, structural basis for rRNA interaction established","pmids":["12766408"],"is_preprint":false},{"year":2016,"finding":"RPL23 is induced downstream of oncogenic RAS signaling (requiring both MEK and PI3K pathways and mTOR function), and the resulting elevated RPL23 binds MDM2 (including the MDM2(C305F) mutant that is deficient for RPL11 binding) to activate p53. Downregulation of RPL23 abolishes RAS-induced p53 activation, establishing a RPL23-MDM2-p53 pathway specific to oncogenic RAS-induced tumor suppression.","method":"Mouse genetic crosses (MDM2(C305F) mutant x Hras(G12V) transgene), siRNA knockdown, pathway inhibitor experiments (MEK, PI3K, mTOR inhibitors), co-IP","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetics plus multiple pathway inhibitors plus co-IP, single lab with multiple orthogonal methods","pmids":["27402081"],"is_preprint":false},{"year":2016,"finding":"Bcp1 (yeast ortholog of BCCIP) acts as the nuclear chaperone of Rpl23 in Saccharomyces cerevisiae. Bcp1 dissociates Rpl23 from karyopherins and then associates with Rpl23. Loss of Bcp1 causes instability of Rpl23 and deficiency of 60S ribosomal subunits.","method":"Co-IP, genetic deletion, ribosome profiling/sedimentation, in vivo interaction assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, genetic knockout, ribosome fractionation with clear molecular phenotype, single lab with multiple orthogonal methods","pmids":["27913624"],"is_preprint":false},{"year":2014,"finding":"The beta-isoform of BCCIP (BCCIPβ), but not BCCIPα, forms a ternary complex with RPL23/uL14 and the pre-60S trans-acting factor eIF6. Complex formation requires an intact C-terminal domain of BCCIPβ. Depletion of BCCIPβ reduces the pool of free RPL23 and decreases eIF6 levels in nucleoli. Overexpression of BCCIPβ leads to nucleoplasmic accumulation of extra-ribosomal RPL23 and stabilizes overexpressed RPL23, indicating BCCIPβ is a nuclear chaperone for RPL23.","method":"Co-IP (reciprocal), siRNA depletion, subcellular fractionation, overexpression assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, depletion and overexpression with orthogonal readouts, single lab","pmids":["25150171"],"is_preprint":false},{"year":2018,"finding":"GRWD1 interacts with RPL23 and, together with the E3 ubiquitin ligase EDD/UBR5, promotes RPL23 ubiquitylation and proteasomal degradation. Overexpression of GRWD1 decreases RPL23 protein levels and stability (reversed by MG132); siRNA knockdown of GRWD1 upregulates RPL23. This GRWD1-induced RPL23 proteolysis downregulates p53.","method":"Co-IP/proteomics, siRNA knockdown, proteasome inhibitor (MG132) rescue, ubiquitylation assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitylation assay, proteasome inhibitor rescue, loss-of-function knockdown, single lab with multiple orthogonal methods","pmids":["29991511"],"is_preprint":false},{"year":2023,"finding":"The C-terminal tail of uL14 (RPL23) is essential for its physical interaction with eIF6 at the 60S ribosomal subunit interface, involving eight key residues. Disease-associated SDS mutations in eIF6 cause conformational changes that weaken the eIF6-uL14 interface. HDX-MS revealed dynamic configurational rearrangements in eIF6 upon binding to uL14 and an allosteric interface regulated by the eIF6 C-tail. Disrupting this interface markedly limits cancer cell proliferation.","method":"Recombinant protein interaction assays, hydrogen-deuterium exchange mass spectrometry (HDX-MS), mutagenesis, cell proliferation assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — HDX-MS with mutagenesis identifying key interface residues, functional validation by cell proliferation, single lab","pmids":["36651285"],"is_preprint":false},{"year":2019,"finding":"Loss of FBXO7 in midbrain dopamine neurons leads to increased expression of RPL23, which inhibits MDM2 as a ribosomal stress sensor, activating a p53 transcriptional signature biased toward pro-apoptotic genes. This establishes the RPL23-MDM2-p53 axis as a mechanism underlying dopaminergic cell death in a Parkinson's disease mouse model.","method":"Conditional knockout mouse model, immunohistochemistry, transcriptional profiling","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo conditional knockout with molecular pathway readout, but pathway placement relies on prior mechanistic work; single lab, transcriptional evidence without direct MDM2 binding confirmed in this study","pmids":["31144295"],"is_preprint":false},{"year":2017,"finding":"RPL23 knockdown in MDS cells led to increased apoptosis, G1-S arrest, upregulation of Miz-1 with transactivation of p15Ink4b and p21Cip1, and downregulation of c-Myc. Cells from higher-risk MDS patients showed elevated RPL23 and c-Myc with decreased Miz-1. This establishes an RPL23/Miz-1/c-Myc regulatory circuit where elevated RPL23 suppresses Miz-1-dependent CDK inhibitor induction.","method":"siRNA knockdown, gene microarray, flow cytometry, Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with gene expression profiling and pathway confirmation, consistent with prior mechanistic work, single lab","pmids":["28539603"],"is_preprint":false},{"year":2004,"finding":"Overexpression of RPL23 in gastric cancer cells enhanced resistance to multiple drugs (vincristine, adriamycin, 5-fluorouracil, cisplatin) by protecting cells from vincristine-induced apoptosis. RPL23 overexpression significantly increased Bcl-2 expression and Bcl-2/Bax ratio, and also enhanced glutathione S-transferase (GST) activity and intracellular glutathione content.","method":"Stable overexpression, drug sensitivity assays, Western blot, enzyme activity assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with multiple drug and molecular readouts, but mechanism is correlative (no direct protein interaction established); single lab","pmids":["15149863"],"is_preprint":false},{"year":2020,"finding":"Triptolide (TP) interrupts rRNA synthesis by inhibiting RNA Pol I and UBF transcriptional activation, inducing nucleolar disintegration. This ribosomal stress increases binding of RPL23 to MDM2, releasing and stabilizing p53, which then induces apoptosis and cell cycle arrest.","method":"Co-IP, Western blot, RNA Pol I activity assay, immunofluorescence, in vivo xenograft","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP showing RPL23-MDM2 binding increase, mechanistic pathway with in vitro and in vivo evidence, single lab","pmids":["32236588"],"is_preprint":false},{"year":1984,"finding":"E. coli ribosomal protein L23 is the primary ribosomal protein crosslinked to affinity-labeled puromycin, placing it within the A-site domain of the peptidyl transferase centre on the 50S subunit. The RNA binding site of L23 consists of two main fragments of 25 and 105 nucleotides that strongly interact. Chemical probing showed altered reactivity of many nucleotides upon L23 binding, indicating large-scale RNA-protein contacts at the extremities of helices and at bulged nucleotides.","method":"Affinity labeling with puromycin, RNA footprinting with chemical reagents and ribonucleases, RNA sequencing","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — chemical footprinting with affinity labeling, multiple probes, single lab","pmids":["6392564"],"is_preprint":false},{"year":1990,"finding":"Puromycin-labeled L23 reconstituted into E. coli 50S subunits retains virtually all peptidyl transferase activity but only 50–60% of mRNA-dependent tRNA binding stimulation activity. This indicates L23 is positioned close to (but not directly at) the peptidyl transferase center, and is close enough to interfere with tRNA binding when modified.","method":"50S ribosome reconstitution with modified L23, peptidyl transferase assay, tRNA binding assay","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with functional assays, single lab","pmids":["2191716"],"is_preprint":false},{"year":1997,"finding":"Electron microscopy localized DNP-modified L23 to two sites on the E. coli 50S subunit with nearly equal frequency: one beside the central protuberance near the peptidyltransferase center, and a second at the base of the subunit near the peptide exit site. This indicates L23 spans the interior tunnel linking the transferase and exit sites.","method":"Reconstitution of 50S with DNP-L23, immune electron microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immune EM with reconstituted subunits, two major localization sites identified, single lab","pmids":["9079702"],"is_preprint":false},{"year":1991,"finding":"Chemical and ribonuclease footprinting of E. coli 23S rRNA revealed that L23 binding is confined to a tertiary structural motif involving a single terminal loop structure and part of an adjacent internal loop at the centre of domain III. L23 is essential for ribosomal assembly and influences secondary binding protein assembly and function of the RNA region.","method":"Chemical footprinting, ribonuclease protection assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple chemical probes and ribonucleases, single lab","pmids":["1960726"],"is_preprint":false},{"year":2021,"finding":"RPL23 directly associates with the 3'UTR of MMP9 mRNA and positively regulates MMP9 expression, promoting HCC cell invasion and metastasis. RPL23 depletion inhibited HCC cell proliferation, migration, invasion, and distant metastasis.","method":"RNA immunoprecipitation (RIP), siRNA knockdown, invasion/migration assays, in vivo metastasis model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP assay for direct RNA binding, knockdown with functional readouts, single lab, single method for the binding claim","pmids":["34926291"],"is_preprint":false},{"year":2024,"finding":"U2AF2-SNORA68 promotes retention of RPL23 in the nucleolus by binding U2AF2. Nucleolar RPL23 subsequently upregulates c-Myc expression. Elevated SNORA68 leads to increased nucleolar RPL23, and this pathway promotes triple-negative breast cancer stemness.","method":"RNA pull-down, RIP, cell fractionation, co-IP, xenograft model","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary methods (RIP, fractionation, co-IP), in vivo validation, single lab","pmids":["38594783"],"is_preprint":false},{"year":1981,"finding":"RNA-protein crosslinking in E. coli ribosomes identified L23 as crosslinked to positions 137-141 in the 23S RNA sequence, localizing the RNA contact site of L23 within 23S rRNA.","method":"2-iminothiolane crosslinking followed by UV irradiation, RNA sequencing of crosslinked fragments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical crosslinking with site identification, single lab","pmids":["6170935"],"is_preprint":false},{"year":2025,"finding":"In extracto cryo-EM at ~2.2 Å resolution showed that elongation factor eEF2•GDP is stabilized on hibernating (non-translating) ribosomes through interactions with the sarcin-ricin loop and protein uL14 (RPL23). eEF2 was found bound to >95% of hibernating ribosomes and unexpectedly also to isolated 60S subunits.","method":"In extracto cryo-EM, high-resolution 2D template matching","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — near-atomic resolution cryo-EM structure, single preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.11.25.690450"],"is_preprint":true},{"year":2025,"finding":"Loss of uL14 (RPL23) significantly downregulates antigen processing and presentation (APP) components in melanoma cells, alters the peptide pool available for MHC/HLA presentation (altered charge, anchor residues, lower predicted HLA binding), and reduces the ability of CD8+ T cells to recognize and kill melanoma cells in co-culture.","method":"siRNA knockdown, proteomics/peptide analysis, co-culture cytotoxicity assay","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with multiple orthogonal readouts (proteomics, peptidome, functional T cell killing assay), single lab","pmids":["40918646"],"is_preprint":false},{"year":2025,"finding":"High-speed atomic force microscopy visualized Trigger Factor (TF) making dynamic stable and transient contacts with ribosomal proteins uL23 and bL17 specifically in ribosome-nascent chain complexes (not on non-translating ribosomes). TF exhibited transitions between extended and compact conformations during this interaction.","method":"High-speed atomic force microscopy, molecular dynamics simulations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct real-time imaging at near-physiological conditions, single preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.16.654432"],"is_preprint":true}],"current_model":"RPL23/uL14 is a ribosomal large subunit protein located at the peptide exit tunnel that serves as a docking site for co-translational chaperones (Trigger Factor, SRP, NAC) and assembly factors (eIF6, via a C-terminal tail interface stabilized by BCCIPβ); under ribosomal stress it dissociates from the ribosome and binds the central acidic domain of MDM2/HDM2 to inhibit p53 ubiquitination and degradation, thereby activating p53-dependent cell cycle arrest—a pathway specifically engaged downstream of oncogenic RAS (via MEK/PI3K/mTOR-driven RPL23 upregulation) and regulated by GRWD1/EDD-mediated ubiquitin-proteasomal degradation of RPL23; extra-ribosomal RPL23 also modulates the Miz1/c-Myc/nucleophosmin circuit to control cell proliferation, and its loss alters antigen presentation to enable tumor immune escape."},"narrative":{"mechanistic_narrative":"RPL23/uL14 is a large-subunit ribosomal protein that performs dual structural and regulatory roles, positioned at the peptide exit tunnel where it both anchors co-translational factors and, when extra-ribosomal, controls the p53 pathway [PMID:15314173, PMID:12226666]. Structurally it occupies the interior of the 50S/60S subunit, with a flexible loop that rigidifies upon rRNA binding to form part of the exit tunnel wall, spanning the region between the peptidyl transferase center and the peptide exit site [PMID:12766408, PMID:9079702]. At the exit tunnel it serves as the essential docking platform for nascent-chain-processing factors—Trigger Factor, SRP, and the nascent polypeptide-associated complex—which contact L23 and compete for this surface [PMID:12226666, PMID:12756233, PMID:16316984]. Its C-terminal tail forms an interface with the anti-association factor eIF6 at the subunit interface, an interaction required for cancer cell proliferation, while nuclear chaperoning of free RPL23 by BCCIPβ stabilizes the protein and supports 60S biogenesis [PMID:36651285, PMID:25150171, PMID:27913624]. Beyond the ribosome, RPL23 is a sensor of ribosomal/nucleolar stress: it dissociates and binds the central acidic domain of MDM2/HDM2 to block MDM2-mediated p53 ubiquitination and degradation, triggering p53-dependent G1 arrest [PMID:15314173, PMID:15314174]. This RPL23–MDM2–p53 axis is engaged downstream of oncogenic RAS signaling, which upregulates RPL23 via MEK/PI3K/mTOR [PMID:27402081], and is set by GRWD1/EDD-mediated ubiquitin-proteasomal turnover of RPL23 [PMID:29991511]. RPL23 additionally restrains the Miz1/c-Myc/nucleophosmin circuit by retaining nucleophosmin in the nucleolus to suppress Miz1-driven induction of the CDK inhibitors p15(Ink4b) and p21(Cip1), forming a Myc-responsive feedback loop coupling growth to cell-cycle control [PMID:19160485, PMID:28539603]. Loss of RPL23 also downregulates antigen processing and presentation, impairing CD8+ T cell recognition of tumor cells [PMID:40918646].","teleology":[{"year":1984,"claim":"Establishing where L23 sits in the ribosome was the first mechanistic question; affinity labeling placed it within the A-site/peptidyl transferase domain of the 50S subunit with extensive rRNA contacts.","evidence":"Puromycin affinity labeling and chemical/ribonuclease RNA footprinting in E. coli","pmids":["6392564"],"confidence":"Medium","gaps":["Resolution insufficient to define exit-tunnel role","rRNA binding site mapped only at the fragment level"]},{"year":1997,"claim":"Refining its position resolved that L23 spans the interior tunnel linking the transferase center to the peptide exit site, foreshadowing its role at the nascent-chain emergence point.","evidence":"Immune electron microscopy of reconstituted 50S subunits with DNP-modified L23, plus reconstitution functional assays","pmids":["9079702","2191716","1960726","6170935"],"confidence":"Medium","gaps":["Two localization sites observed without single high-resolution placement","Functional consequence at the exit tunnel not yet tested"]},{"year":2002,"claim":"The exit-tunnel positioning was given function: L23 is the essential docking site for Trigger Factor, coupling the protein to co-translational chaperone delivery.","evidence":"Crosslinking, in vitro binding, site-directed mutagenesis and genetic complementation in E. coli","pmids":["12226666"],"confidence":"High","gaps":["Whether the same surface accommodates other factors not yet defined here","Eukaryotic generalization untested in this study"]},{"year":2003,"claim":"L23 was shown to be a shared, competed-for hub for multiple targeting factors, establishing it as a regulatory node for nascent-chain fate at the exit site.","evidence":"Site-specific UV crosslinking and competitive in vitro binding assays mapping SRP/Ffh and Trigger Factor to L23; NMR solution structure of L23","pmids":["12702815","12756233","12766408"],"confidence":"High","gaps":["Competition outcome on actively translating ribosomes not fully resolved","Structural basis of factor discrimination not defined"]},{"year":2004,"claim":"The discovery that L23 binds the central acidic domain of MDM2/HDM2 independent of the ribosome answered how a structural ribosomal protein signals stress, revealing an extra-ribosomal p53-stabilizing function.","evidence":"Immunoaffinity purification, domain-mapped reciprocal co-IP, p53 ubiquitination assays, siRNA knockdown and flow cytometry in human cells","pmids":["15314173","15314174"],"confidence":"High","gaps":["Trigger that releases L23 from the ribosome not mechanistically defined","Stoichiometry within the L11/L23/MDM2 ternary complex unresolved"]},{"year":2004,"claim":"An additional cancer phenotype was linked to RPL23 — multidrug resistance — though through correlative anti-apoptotic and detoxification changes rather than a defined molecular interaction.","evidence":"Stable overexpression in gastric cancer cells, drug sensitivity assays, Western blot, enzyme activity assays","pmids":["15149863"],"confidence":"Medium","gaps":["No direct protein interaction established for the resistance phenotype","Causal link to Bcl-2/GST changes correlative"]},{"year":2008,"claim":"RPL23 was tied to a second growth-control circuit: it suppresses Miz1 transactivation by sequestering nucleophosmin in the nucleolus, and is itself a Myc target, forming a translation-to-cell-cycle feedback loop.","evidence":"Co-IP, nucleolar retention assays, Miz1 reporter assays and knockdown","pmids":["19160485"],"confidence":"High","gaps":["How nucleophosmin partitioning is dynamically regulated unclear","Crosstalk with the MDM2/p53 axis not integrated"]},{"year":2014,"claim":"The biogenesis side of RPL23 was clarified: BCCIPβ acts as a nuclear chaperone that stabilizes free RPL23 and forms a ternary complex with the 60S factor eIF6.","evidence":"Reciprocal co-IP, siRNA depletion, subcellular fractionation and overexpression in human cells; yeast Bcp1 genetics","pmids":["25150171","27913624"],"confidence":"High","gaps":["Whether chaperoning competes with the extra-ribosomal MDM2 pool unknown","Structural basis of the BCCIPβ C-terminal requirement undefined at this stage"]},{"year":2016,"claim":"The RPL23–MDM2–p53 axis was placed in an oncogenic signaling context, showing RAS drives RPL23 upregulation through MEK/PI3K/mTOR to activate p53 as tumor suppression.","evidence":"Mouse genetics (MDM2 C305F x Hras G12V), pathway inhibitors, siRNA and co-IP","pmids":["27402081"],"confidence":"High","gaps":["Direct transcriptional/translational mechanism of RPL23 induction not fully resolved","Relative contribution versus other ribosomal stress sensors unquantified"]},{"year":2018,"claim":"RPL23 abundance was shown to be set by regulated proteolysis, with GRWD1 and the E3 ligase EDD/UBR5 driving its ubiquitin-proteasomal degradation to dampen p53.","evidence":"Co-IP/proteomics, ubiquitylation assay, MG132 rescue and siRNA in human cells","pmids":["29991511"],"confidence":"High","gaps":["Signals controlling GRWD1/EDD activity toward RPL23 unknown","Selectivity for free versus ribosome-bound RPL23 unaddressed"]},{"year":2019,"claim":"The RPL23–MDM2–p53 axis was extended to a disease context beyond cancer, implicating it in dopaminergic neuron death downstream of FBXO7 loss.","evidence":"Conditional knockout mouse model, immunohistochemistry, transcriptional profiling","pmids":["31144295"],"confidence":"Medium","gaps":["Direct RPL23-MDM2 binding not confirmed in this study","Pathway placement relies on prior mechanistic work"]},{"year":2021,"claim":"An RNA-regulatory function emerged: RPL23 binds the MMP9 3'UTR to promote its expression and drive HCC invasion and metastasis.","evidence":"RNA immunoprecipitation, siRNA knockdown, invasion/migration and in vivo metastasis assays","pmids":["34926291"],"confidence":"Medium","gaps":["Binding shown by a single method (RIP) without reciprocal validation","Mechanism of mRNA stabilization/translation not defined"]},{"year":2023,"claim":"The RPL23–eIF6 interface was mapped to the uL14 C-terminal tail, defining eight key residues and linking interface disruption to suppression of cancer cell proliferation.","evidence":"Recombinant interaction assays, HDX-MS, mutagenesis and proliferation assays","pmids":["36651285"],"confidence":"High","gaps":["In vivo consequence of interface disruption untested","Connection to SDS disease mechanism characterized only via eIF6 mutants"]},{"year":2024,"claim":"Nucleolar retention of RPL23 was shown to be actively regulated, via U2AF2-SNORA68, with nucleolar RPL23 upregulating c-Myc to promote breast cancer stemness.","evidence":"RNA pull-down, RIP, fractionation, co-IP and xenograft","pmids":["38594783"],"confidence":"Medium","gaps":["Molecular mechanism of c-Myc upregulation by nucleolar RPL23 unclear","Relationship to the Miz1/nucleophosmin circuit not integrated"]},{"year":2025,"claim":"A new cell-extrinsic role was uncovered: RPL23 loss downregulates antigen processing/presentation and impairs CD8+ T cell killing, linking ribosomal protein levels to tumor immune escape.","evidence":"siRNA knockdown, proteomics/peptidome analysis, T cell co-culture cytotoxicity assay in melanoma cells","pmids":["40918646"],"confidence":"Medium","gaps":["Mechanism linking RPL23 to APP gene expression undefined","Whether effect depends on global translation or a specific pathway unknown"]},{"year":null,"claim":"How RPL23 is partitioned between its ribosomal, nuclear-chaperoned, and extra-ribosomal (MDM2/Miz1/RNA-binding) pools, and what dictates which function dominates under a given stress, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling exit-tunnel occupancy to stress release","Quantitative control of free versus ribosome-bound RPL23 unmeasured","Eukaryotic structural basis for exit-tunnel chaperone docking not directly established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,7,17,19]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[21,17,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,5]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[2,7,17,19]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,6,10,22]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,4,5,12,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,6,8,14]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,16]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25]}],"complexes":["60S large ribosomal subunit","L11/L23/MDM2 ternary complex","RPL23-BCCIPβ-eIF6 ternary complex"],"partners":["MDM2","EIF6","BCCIP","GRWD1","UBR5","NPM1","U2AF2","EEF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62829","full_name":"Large ribosomal subunit protein uL14","aliases":["60S ribosomal protein L17","60S ribosomal protein L23"],"length_aa":140,"mass_kda":14.9,"function":"Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P62829/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL23","classification":"Common 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This interaction is enhanced by actinomycin D (ribosomal perturbation) but not gamma-irradiation. Ectopic L23 expression reduces MDM2-mediated p53 ubiquitination and induces p53 activity and G1 arrest in p53-proficient cells; siRNA knockdown of L23 abolishes this activation.\",\n      \"method\": \"Immunoaffinity purification, co-IP, siRNA knockdown, ubiquitination assay, flow cytometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, loss-of-function siRNA, ubiquitination assay, replicated in companion paper same year\",\n      \"pmids\": [\"15314173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RPL23 (L23) interacts with HDM2 through the central acidic domain of HDM2 and an N-terminal domain of L23. L23 and L11 can simultaneously yet distinctly bind HDM2, forming a ternary complex. Overexpressed L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes p53-dependent cell cycle arrest. Knockdown of L23 triggers nucleolar stress, translocation of B23 from nucleolus to nucleoplasm, and stabilization/activation of p53.\",\n      \"method\": \"Co-IP, domain-mapping experiments, p53 ubiquitination assay, siRNA knockdown, flow cytometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-mapped co-IP, ubiquitination assay, loss-of-function knockdown, replicated by companion paper\",\n      \"pmids\": [\"15314174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In E. coli, L23 (bacterial ortholog of RPL23/uL14) is located at the ribosomal peptide exit tunnel and serves as an essential docking site for the chaperone Trigger Factor. Mutation of an exposed glutamate in L23 prevents Trigger Factor from interacting with ribosomes and nascent chains, causes protein aggregation, and causes conditional lethality. Purified L23 interacts specifically with Trigger Factor in vitro.\",\n      \"method\": \"Crosslinking, in vitro binding assay, mutagenesis, genetic complementation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, site-directed mutagenesis, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"12226666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The signal recognition particle (SRP) component Ffh crosslinks to ribosomal protein L23 at the peptide exit of the E. coli 50S subunit. Two positions in the N domain of Ffh crosslink predominantly to L23. Binding of a nascent signal peptide induces a slightly different arrangement of SRP on L23.\",\n      \"method\": \"Site-specific UV-induced crosslinking (p-azidophenacyl bromide), biochemical mapping\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific crosslinking with engineered cysteines, multiple positions tested, single lab\",\n      \"pmids\": [\"12702815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Both Trigger Factor (TF) and SRP interact with the signal anchor sequence of nascent inner membrane proteins and contact L23 and L29 at the ribosomal exit site. TF and SRP compete for binding to L23 on non-translating ribosomes, with SRP having a competitive advantage.\",\n      \"method\": \"Photocrosslinking of nascent chains, in vitro binding assay with purified components\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — photocrosslinking with in vitro reconstitution, competitive binding assay, single lab\",\n      \"pmids\": [\"12756233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The nascent polypeptide-associated complex (NAC) contacts L23 (ribosomal protein family member) at the ribosomal exit site via a conserved RRK(X)nKK ribosome-binding motif in the β-subunit of NAC. UV-crosslinking of the motif specifically crosslinks to L23 at the exit site. Mutations of L23 reduce NAC ribosome binding in vivo and in vitro without affecting other ribosome-associated factors (Ssb, Zuotin).\",\n      \"method\": \"UV-activatable crosslinking, mutagenesis of L23, in vivo and in vitro binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crosslinking with mutagenesis, both in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"16316984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RPL23 functions as a negative regulator of Miz1-dependent transactivation by retaining nucleophosmin (an essential co-activator of Miz1) in the nucleolus, thereby preventing Miz1-induced expression of cell-cycle inhibitors p15(Ink4b) and p21(Cip1). RPL23 is encoded by a direct Myc target gene, forming a feedback circuit linking translation/cell growth with Miz1-dependent cell-cycle arrest.\",\n      \"method\": \"Co-IP, nucleolar retention assay, reporter assays for Miz1 transactivation, knockdown experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, subcellular fractionation showing nucleolar retention, loss-of-function with defined molecular phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19160485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NMR structure of ribosomal protein L23 from Thermus thermophilus determined in solution. Uncomplexed L23 has a well-ordered core (four anti-parallel beta-strands and three alpha-helices in a beta-alpha-beta-alpha-beta-beta-alpha topology) with a large flexible loop between strands 3 and 4. In RNA-complexed crystal structures, this flexible loop becomes rigid and forms part of the ribosomal exit tunnel wall through interactions with rRNA.\",\n      \"method\": \"NMR structure determination, comparison with crystal structures\",\n      \"journal\": \"Journal of biomolecular NMR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional comparison to crystal structures, structural basis for rRNA interaction established\",\n      \"pmids\": [\"12766408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RPL23 is induced downstream of oncogenic RAS signaling (requiring both MEK and PI3K pathways and mTOR function), and the resulting elevated RPL23 binds MDM2 (including the MDM2(C305F) mutant that is deficient for RPL11 binding) to activate p53. Downregulation of RPL23 abolishes RAS-induced p53 activation, establishing a RPL23-MDM2-p53 pathway specific to oncogenic RAS-induced tumor suppression.\",\n      \"method\": \"Mouse genetic crosses (MDM2(C305F) mutant x Hras(G12V) transgene), siRNA knockdown, pathway inhibitor experiments (MEK, PI3K, mTOR inhibitors), co-IP\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetics plus multiple pathway inhibitors plus co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27402081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bcp1 (yeast ortholog of BCCIP) acts as the nuclear chaperone of Rpl23 in Saccharomyces cerevisiae. Bcp1 dissociates Rpl23 from karyopherins and then associates with Rpl23. Loss of Bcp1 causes instability of Rpl23 and deficiency of 60S ribosomal subunits.\",\n      \"method\": \"Co-IP, genetic deletion, ribosome profiling/sedimentation, in vivo interaction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, genetic knockout, ribosome fractionation with clear molecular phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27913624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The beta-isoform of BCCIP (BCCIPβ), but not BCCIPα, forms a ternary complex with RPL23/uL14 and the pre-60S trans-acting factor eIF6. Complex formation requires an intact C-terminal domain of BCCIPβ. Depletion of BCCIPβ reduces the pool of free RPL23 and decreases eIF6 levels in nucleoli. Overexpression of BCCIPβ leads to nucleoplasmic accumulation of extra-ribosomal RPL23 and stabilizes overexpressed RPL23, indicating BCCIPβ is a nuclear chaperone for RPL23.\",\n      \"method\": \"Co-IP (reciprocal), siRNA depletion, subcellular fractionation, overexpression assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, depletion and overexpression with orthogonal readouts, single lab\",\n      \"pmids\": [\"25150171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GRWD1 interacts with RPL23 and, together with the E3 ubiquitin ligase EDD/UBR5, promotes RPL23 ubiquitylation and proteasomal degradation. Overexpression of GRWD1 decreases RPL23 protein levels and stability (reversed by MG132); siRNA knockdown of GRWD1 upregulates RPL23. This GRWD1-induced RPL23 proteolysis downregulates p53.\",\n      \"method\": \"Co-IP/proteomics, siRNA knockdown, proteasome inhibitor (MG132) rescue, ubiquitylation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitylation assay, proteasome inhibitor rescue, loss-of-function knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29991511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The C-terminal tail of uL14 (RPL23) is essential for its physical interaction with eIF6 at the 60S ribosomal subunit interface, involving eight key residues. Disease-associated SDS mutations in eIF6 cause conformational changes that weaken the eIF6-uL14 interface. HDX-MS revealed dynamic configurational rearrangements in eIF6 upon binding to uL14 and an allosteric interface regulated by the eIF6 C-tail. Disrupting this interface markedly limits cancer cell proliferation.\",\n      \"method\": \"Recombinant protein interaction assays, hydrogen-deuterium exchange mass spectrometry (HDX-MS), mutagenesis, cell proliferation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — HDX-MS with mutagenesis identifying key interface residues, functional validation by cell proliferation, single lab\",\n      \"pmids\": [\"36651285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of FBXO7 in midbrain dopamine neurons leads to increased expression of RPL23, which inhibits MDM2 as a ribosomal stress sensor, activating a p53 transcriptional signature biased toward pro-apoptotic genes. This establishes the RPL23-MDM2-p53 axis as a mechanism underlying dopaminergic cell death in a Parkinson's disease mouse model.\",\n      \"method\": \"Conditional knockout mouse model, immunohistochemistry, transcriptional profiling\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo conditional knockout with molecular pathway readout, but pathway placement relies on prior mechanistic work; single lab, transcriptional evidence without direct MDM2 binding confirmed in this study\",\n      \"pmids\": [\"31144295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RPL23 knockdown in MDS cells led to increased apoptosis, G1-S arrest, upregulation of Miz-1 with transactivation of p15Ink4b and p21Cip1, and downregulation of c-Myc. Cells from higher-risk MDS patients showed elevated RPL23 and c-Myc with decreased Miz-1. This establishes an RPL23/Miz-1/c-Myc regulatory circuit where elevated RPL23 suppresses Miz-1-dependent CDK inhibitor induction.\",\n      \"method\": \"siRNA knockdown, gene microarray, flow cytometry, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with gene expression profiling and pathway confirmation, consistent with prior mechanistic work, single lab\",\n      \"pmids\": [\"28539603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Overexpression of RPL23 in gastric cancer cells enhanced resistance to multiple drugs (vincristine, adriamycin, 5-fluorouracil, cisplatin) by protecting cells from vincristine-induced apoptosis. RPL23 overexpression significantly increased Bcl-2 expression and Bcl-2/Bax ratio, and also enhanced glutathione S-transferase (GST) activity and intracellular glutathione content.\",\n      \"method\": \"Stable overexpression, drug sensitivity assays, Western blot, enzyme activity assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with multiple drug and molecular readouts, but mechanism is correlative (no direct protein interaction established); single lab\",\n      \"pmids\": [\"15149863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Triptolide (TP) interrupts rRNA synthesis by inhibiting RNA Pol I and UBF transcriptional activation, inducing nucleolar disintegration. This ribosomal stress increases binding of RPL23 to MDM2, releasing and stabilizing p53, which then induces apoptosis and cell cycle arrest.\",\n      \"method\": \"Co-IP, Western blot, RNA Pol I activity assay, immunofluorescence, in vivo xenograft\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing RPL23-MDM2 binding increase, mechanistic pathway with in vitro and in vivo evidence, single lab\",\n      \"pmids\": [\"32236588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"E. coli ribosomal protein L23 is the primary ribosomal protein crosslinked to affinity-labeled puromycin, placing it within the A-site domain of the peptidyl transferase centre on the 50S subunit. The RNA binding site of L23 consists of two main fragments of 25 and 105 nucleotides that strongly interact. Chemical probing showed altered reactivity of many nucleotides upon L23 binding, indicating large-scale RNA-protein contacts at the extremities of helices and at bulged nucleotides.\",\n      \"method\": \"Affinity labeling with puromycin, RNA footprinting with chemical reagents and ribonucleases, RNA sequencing\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical footprinting with affinity labeling, multiple probes, single lab\",\n      \"pmids\": [\"6392564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Puromycin-labeled L23 reconstituted into E. coli 50S subunits retains virtually all peptidyl transferase activity but only 50–60% of mRNA-dependent tRNA binding stimulation activity. This indicates L23 is positioned close to (but not directly at) the peptidyl transferase center, and is close enough to interfere with tRNA binding when modified.\",\n      \"method\": \"50S ribosome reconstitution with modified L23, peptidyl transferase assay, tRNA binding assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with functional assays, single lab\",\n      \"pmids\": [\"2191716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Electron microscopy localized DNP-modified L23 to two sites on the E. coli 50S subunit with nearly equal frequency: one beside the central protuberance near the peptidyltransferase center, and a second at the base of the subunit near the peptide exit site. This indicates L23 spans the interior tunnel linking the transferase and exit sites.\",\n      \"method\": \"Reconstitution of 50S with DNP-L23, immune electron microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immune EM with reconstituted subunits, two major localization sites identified, single lab\",\n      \"pmids\": [\"9079702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Chemical and ribonuclease footprinting of E. coli 23S rRNA revealed that L23 binding is confined to a tertiary structural motif involving a single terminal loop structure and part of an adjacent internal loop at the centre of domain III. L23 is essential for ribosomal assembly and influences secondary binding protein assembly and function of the RNA region.\",\n      \"method\": \"Chemical footprinting, ribonuclease protection assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple chemical probes and ribonucleases, single lab\",\n      \"pmids\": [\"1960726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RPL23 directly associates with the 3'UTR of MMP9 mRNA and positively regulates MMP9 expression, promoting HCC cell invasion and metastasis. RPL23 depletion inhibited HCC cell proliferation, migration, invasion, and distant metastasis.\",\n      \"method\": \"RNA immunoprecipitation (RIP), siRNA knockdown, invasion/migration assays, in vivo metastasis model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP assay for direct RNA binding, knockdown with functional readouts, single lab, single method for the binding claim\",\n      \"pmids\": [\"34926291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"U2AF2-SNORA68 promotes retention of RPL23 in the nucleolus by binding U2AF2. Nucleolar RPL23 subsequently upregulates c-Myc expression. Elevated SNORA68 leads to increased nucleolar RPL23, and this pathway promotes triple-negative breast cancer stemness.\",\n      \"method\": \"RNA pull-down, RIP, cell fractionation, co-IP, xenograft model\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary methods (RIP, fractionation, co-IP), in vivo validation, single lab\",\n      \"pmids\": [\"38594783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1981,\n      \"finding\": \"RNA-protein crosslinking in E. coli ribosomes identified L23 as crosslinked to positions 137-141 in the 23S RNA sequence, localizing the RNA contact site of L23 within 23S rRNA.\",\n      \"method\": \"2-iminothiolane crosslinking followed by UV irradiation, RNA sequencing of crosslinked fragments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical crosslinking with site identification, single lab\",\n      \"pmids\": [\"6170935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In extracto cryo-EM at ~2.2 Å resolution showed that elongation factor eEF2•GDP is stabilized on hibernating (non-translating) ribosomes through interactions with the sarcin-ricin loop and protein uL14 (RPL23). eEF2 was found bound to >95% of hibernating ribosomes and unexpectedly also to isolated 60S subunits.\",\n      \"method\": \"In extracto cryo-EM, high-resolution 2D template matching\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — near-atomic resolution cryo-EM structure, single preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.25.690450\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of uL14 (RPL23) significantly downregulates antigen processing and presentation (APP) components in melanoma cells, alters the peptide pool available for MHC/HLA presentation (altered charge, anchor residues, lower predicted HLA binding), and reduces the ability of CD8+ T cells to recognize and kill melanoma cells in co-culture.\",\n      \"method\": \"siRNA knockdown, proteomics/peptide analysis, co-culture cytotoxicity assay\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with multiple orthogonal readouts (proteomics, peptidome, functional T cell killing assay), single lab\",\n      \"pmids\": [\"40918646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"High-speed atomic force microscopy visualized Trigger Factor (TF) making dynamic stable and transient contacts with ribosomal proteins uL23 and bL17 specifically in ribosome-nascent chain complexes (not on non-translating ribosomes). TF exhibited transitions between extended and compact conformations during this interaction.\",\n      \"method\": \"High-speed atomic force microscopy, molecular dynamics simulations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct real-time imaging at near-physiological conditions, single preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.16.654432\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPL23/uL14 is a ribosomal large subunit protein located at the peptide exit tunnel that serves as a docking site for co-translational chaperones (Trigger Factor, SRP, NAC) and assembly factors (eIF6, via a C-terminal tail interface stabilized by BCCIPβ); under ribosomal stress it dissociates from the ribosome and binds the central acidic domain of MDM2/HDM2 to inhibit p53 ubiquitination and degradation, thereby activating p53-dependent cell cycle arrest—a pathway specifically engaged downstream of oncogenic RAS (via MEK/PI3K/mTOR-driven RPL23 upregulation) and regulated by GRWD1/EDD-mediated ubiquitin-proteasomal degradation of RPL23; extra-ribosomal RPL23 also modulates the Miz1/c-Myc/nucleophosmin circuit to control cell proliferation, and its loss alters antigen presentation to enable tumor immune escape.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL23/uL14 is a large-subunit ribosomal protein that performs dual structural and regulatory roles, positioned at the peptide exit tunnel where it both anchors co-translational factors and, when extra-ribosomal, controls the p53 pathway [#0, #2]. Structurally it occupies the interior of the 50S/60S subunit, with a flexible loop that rigidifies upon rRNA binding to form part of the exit tunnel wall, spanning the region between the peptidyl transferase center and the peptide exit site [#7, #19]. At the exit tunnel it serves as the essential docking platform for nascent-chain-processing factors—Trigger Factor, SRP, and the nascent polypeptide-associated complex—which contact L23 and compete for this surface [#2, #4, #5]. Its C-terminal tail forms an interface with the anti-association factor eIF6 at the subunit interface, an interaction required for cancer cell proliferation, while nuclear chaperoning of free RPL23 by BCCIPβ stabilizes the protein and supports 60S biogenesis [#12, #10, #9]. Beyond the ribosome, RPL23 is a sensor of ribosomal/nucleolar stress: it dissociates and binds the central acidic domain of MDM2/HDM2 to block MDM2-mediated p53 ubiquitination and degradation, triggering p53-dependent G1 arrest [#0, #1]. This RPL23–MDM2–p53 axis is engaged downstream of oncogenic RAS signaling, which upregulates RPL23 via MEK/PI3K/mTOR [#8], and is set by GRWD1/EDD-mediated ubiquitin-proteasomal turnover of RPL23 [#11]. RPL23 additionally restrains the Miz1/c-Myc/nucleophosmin circuit by retaining nucleophosmin in the nucleolus to suppress Miz1-driven induction of the CDK inhibitors p15(Ink4b) and p21(Cip1), forming a Myc-responsive feedback loop coupling growth to cell-cycle control [#6, #14]. Loss of RPL23 also downregulates antigen processing and presentation, impairing CD8+ T cell recognition of tumor cells [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Establishing where L23 sits in the ribosome was the first mechanistic question; affinity labeling placed it within the A-site/peptidyl transferase domain of the 50S subunit with extensive rRNA contacts.\",\n      \"evidence\": \"Puromycin affinity labeling and chemical/ribonuclease RNA footprinting in E. coli\",\n      \"pmids\": [\"6392564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Resolution insufficient to define exit-tunnel role\", \"rRNA binding site mapped only at the fragment level\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Refining its position resolved that L23 spans the interior tunnel linking the transferase center to the peptide exit site, foreshadowing its role at the nascent-chain emergence point.\",\n      \"evidence\": \"Immune electron microscopy of reconstituted 50S subunits with DNP-modified L23, plus reconstitution functional assays\",\n      \"pmids\": [\"9079702\", \"2191716\", \"1960726\", \"6170935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two localization sites observed without single high-resolution placement\", \"Functional consequence at the exit tunnel not yet tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The exit-tunnel positioning was given function: L23 is the essential docking site for Trigger Factor, coupling the protein to co-translational chaperone delivery.\",\n      \"evidence\": \"Crosslinking, in vitro binding, site-directed mutagenesis and genetic complementation in E. coli\",\n      \"pmids\": [\"12226666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same surface accommodates other factors not yet defined here\", \"Eukaryotic generalization untested in this study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"L23 was shown to be a shared, competed-for hub for multiple targeting factors, establishing it as a regulatory node for nascent-chain fate at the exit site.\",\n      \"evidence\": \"Site-specific UV crosslinking and competitive in vitro binding assays mapping SRP/Ffh and Trigger Factor to L23; NMR solution structure of L23\",\n      \"pmids\": [\"12702815\", \"12756233\", \"12766408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Competition outcome on actively translating ribosomes not fully resolved\", \"Structural basis of factor discrimination not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The discovery that L23 binds the central acidic domain of MDM2/HDM2 independent of the ribosome answered how a structural ribosomal protein signals stress, revealing an extra-ribosomal p53-stabilizing function.\",\n      \"evidence\": \"Immunoaffinity purification, domain-mapped reciprocal co-IP, p53 ubiquitination assays, siRNA knockdown and flow cytometry in human cells\",\n      \"pmids\": [\"15314173\", \"15314174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that releases L23 from the ribosome not mechanistically defined\", \"Stoichiometry within the L11/L23/MDM2 ternary complex unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"An additional cancer phenotype was linked to RPL23 — multidrug resistance — though through correlative anti-apoptotic and detoxification changes rather than a defined molecular interaction.\",\n      \"evidence\": \"Stable overexpression in gastric cancer cells, drug sensitivity assays, Western blot, enzyme activity assays\",\n      \"pmids\": [\"15149863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct protein interaction established for the resistance phenotype\", \"Causal link to Bcl-2/GST changes correlative\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"RPL23 was tied to a second growth-control circuit: it suppresses Miz1 transactivation by sequestering nucleophosmin in the nucleolus, and is itself a Myc target, forming a translation-to-cell-cycle feedback loop.\",\n      \"evidence\": \"Co-IP, nucleolar retention assays, Miz1 reporter assays and knockdown\",\n      \"pmids\": [\"19160485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nucleophosmin partitioning is dynamically regulated unclear\", \"Crosstalk with the MDM2/p53 axis not integrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The biogenesis side of RPL23 was clarified: BCCIPβ acts as a nuclear chaperone that stabilizes free RPL23 and forms a ternary complex with the 60S factor eIF6.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA depletion, subcellular fractionation and overexpression in human cells; yeast Bcp1 genetics\",\n      \"pmids\": [\"25150171\", \"27913624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chaperoning competes with the extra-ribosomal MDM2 pool unknown\", \"Structural basis of the BCCIPβ C-terminal requirement undefined at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The RPL23–MDM2–p53 axis was placed in an oncogenic signaling context, showing RAS drives RPL23 upregulation through MEK/PI3K/mTOR to activate p53 as tumor suppression.\",\n      \"evidence\": \"Mouse genetics (MDM2 C305F x Hras G12V), pathway inhibitors, siRNA and co-IP\",\n      \"pmids\": [\"27402081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional/translational mechanism of RPL23 induction not fully resolved\", \"Relative contribution versus other ribosomal stress sensors unquantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"RPL23 abundance was shown to be set by regulated proteolysis, with GRWD1 and the E3 ligase EDD/UBR5 driving its ubiquitin-proteasomal degradation to dampen p53.\",\n      \"evidence\": \"Co-IP/proteomics, ubiquitylation assay, MG132 rescue and siRNA in human cells\",\n      \"pmids\": [\"29991511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling GRWD1/EDD activity toward RPL23 unknown\", \"Selectivity for free versus ribosome-bound RPL23 unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The RPL23–MDM2–p53 axis was extended to a disease context beyond cancer, implicating it in dopaminergic neuron death downstream of FBXO7 loss.\",\n      \"evidence\": \"Conditional knockout mouse model, immunohistochemistry, transcriptional profiling\",\n      \"pmids\": [\"31144295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RPL23-MDM2 binding not confirmed in this study\", \"Pathway placement relies on prior mechanistic work\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An RNA-regulatory function emerged: RPL23 binds the MMP9 3'UTR to promote its expression and drive HCC invasion and metastasis.\",\n      \"evidence\": \"RNA immunoprecipitation, siRNA knockdown, invasion/migration and in vivo metastasis assays\",\n      \"pmids\": [\"34926291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding shown by a single method (RIP) without reciprocal validation\", \"Mechanism of mRNA stabilization/translation not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The RPL23–eIF6 interface was mapped to the uL14 C-terminal tail, defining eight key residues and linking interface disruption to suppression of cancer cell proliferation.\",\n      \"evidence\": \"Recombinant interaction assays, HDX-MS, mutagenesis and proliferation assays\",\n      \"pmids\": [\"36651285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequence of interface disruption untested\", \"Connection to SDS disease mechanism characterized only via eIF6 mutants\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Nucleolar retention of RPL23 was shown to be actively regulated, via U2AF2-SNORA68, with nucleolar RPL23 upregulating c-Myc to promote breast cancer stemness.\",\n      \"evidence\": \"RNA pull-down, RIP, fractionation, co-IP and xenograft\",\n      \"pmids\": [\"38594783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of c-Myc upregulation by nucleolar RPL23 unclear\", \"Relationship to the Miz1/nucleophosmin circuit not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A new cell-extrinsic role was uncovered: RPL23 loss downregulates antigen processing/presentation and impairs CD8+ T cell killing, linking ribosomal protein levels to tumor immune escape.\",\n      \"evidence\": \"siRNA knockdown, proteomics/peptidome analysis, T cell co-culture cytotoxicity assay in melanoma cells\",\n      \"pmids\": [\"40918646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking RPL23 to APP gene expression undefined\", \"Whether effect depends on global translation or a specific pathway unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RPL23 is partitioned between its ribosomal, nuclear-chaperoned, and extra-ribosomal (MDM2/Miz1/RNA-binding) pools, and what dictates which function dominates under a given stress, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling exit-tunnel occupancy to stress release\", \"Quantitative control of free versus ribosome-bound RPL23 unmeasured\", \"Eukaryotic structural basis for exit-tunnel chaperone docking not directly established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 7, 17, 19]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [21, 17, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [2, 7, 17, 19]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 6, 10, 22]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 4, 5, 12, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 6, 8, 14]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [\n      \"60S large ribosomal subunit\",\n      \"L11/L23/MDM2 ternary complex\",\n      \"RPL23-BCCIPβ-eIF6 ternary complex\"\n    ],\n    \"partners\": [\n      \"MDM2\",\n      \"eIF6\",\n      \"BCCIP\",\n      \"GRWD1\",\n      \"UBR5\",\n      \"NPM1\",\n      \"U2AF2\",\n      \"eEF2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}