{"gene":"RPLP2","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2017,"finding":"RPLP1 and RPLP2 are essential host factors for flavivirus (DENV, YFV, ZIKV) replication; knockdown of RPLP1/2 strongly reduced early DENV protein accumulation and reduced DENV structural proteins expressed from an exogenous transgene, indicating a requirement for these ribosomal stalk proteins in viral translation elongation.","method":"RNA interference knockdown in A549 and HuH-7 cells, metabolic labeling of global protein synthesis, exogenous transgene reporter assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi knockdown, metabolic labeling, transgene reporter), replicated across two human cell lines and in mosquitoes","pmids":["27974556"],"is_preprint":false},{"year":2020,"finding":"RPLP1/2 function to relieve ribosome pausing within sequences encoding multiple adjacent transmembrane domains (TMDs) during translation elongation; ribosome profiling in RPLP1/2-depleted cells showed ribosomes pause in the DENV envelope coding sequence downstream of sequences encoding two adjacent TMDs, and depletion disproportionately affected ribosome density on cellular mRNAs encoding multiple TMDs, implicating RPLP1/2 in multi-pass transmembrane protein biogenesis.","method":"Ribosome profiling (Ribo-seq) in RPLP1/2-depleted cells, analysis of DENV envelope protein stability, global translational analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ribosome profiling provides genome-wide mechanistic resolution, combined with protein stability assays; single lab but multiple orthogonal approaches","pmids":["32890404"],"is_preprint":false},{"year":2023,"finding":"RPLp2 promotes coronavirus (PEDV) mRNA translation in a p-eIF4E-dependent manner; PEDV infection upregulated RPLp2 translation via p-eIF4E, RPLp2 interacted with PEDV 5'UTR through association with eIF4E (shown by RNA binding protein immunoprecipitation), and the viral nucleocapsid protein was recruited into m7GTP-precipitated complexes (cap pull-down) with the assistance of RPLp2, supporting a role for RPLp2 in selective translation initiation of viral mRNA.","method":"TMT quantitative proteomics, bicistronic dual-reporter assay, polysome profiling, RNA binding protein immunoprecipitation, cap (m7GTP) pull-down assay","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (polysome profiling, RIP, cap pull-down) in a single lab","pmids":["36632964"],"is_preprint":false},{"year":2023,"finding":"RPLP2 activates TLR4 on the surface of hepatocellular carcinoma (HCC) cells via autocrine signaling, which activates the downstream PI3K/AKT pathway, facilitating nuclear entry of HIF-1α and its transcriptional activation of glycolytic enzymes, thereby promoting aerobic glycolysis and HCC cell proliferation.","method":"siRNA knockdown of RPLP2, measurement of glycolytic enzyme expression and lactate production, PI3K/AKT pathway inhibition assays, HIF-1α nuclear localization experiments","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — loss-of-function with pathway readouts, but single lab and mechanistic detail (direct TLR4 interaction) not fully validated by binding assay","pmids":["38052785"],"is_preprint":false},{"year":2025,"finding":"METTL14 promotes m6A methylation of RPLP2 mRNA, reducing its stability and thereby suppressing RPLP2 expression in hepatocellular carcinoma; YTHDC2 acts as the m6A reader that decreases RPLP2 expression in this axis, and reduced RPLP2 inhibits HCC cell proliferation, migration, and invasion.","method":"Methylated RNA binding protein immunoprecipitation (MeRIP), dual-luciferase reporter assay, RNA stability determination, METTL14 overexpression and RPLP2 knockdown in HCC cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MeRIP establishes m6A modification on RPLP2 mRNA, RNA stability assay confirms functional consequence; single lab","pmids":["39955344"],"is_preprint":false},{"year":2025,"finding":"RPLP2 knockdown in diffuse large B-cell lymphoma (DLBCL) cells triggers ferroptosis by decreasing expression of the ferroptosis suppressor frataxin (FXN), establishing RPLP2 as a regulator of FXN-mediated ferroptosis in DLBCL.","method":"siRNA knockdown of RPLP2, lipid ROS and iron assays (ferroptosis markers), CCK8 and colony formation assays, xenograft mouse models","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — loss-of-function with specific ferroptosis readouts and in vivo validation; single lab, mechanism linking RPLP2 to FXN not fully elucidated at molecular level","pmids":["40564039"],"is_preprint":false},{"year":2024,"finding":"lncRNA DSCR9 negatively regulates RPLP2 expression (shown by RNA pull-down assay), and RPLP2 acts upstream of PI3K/AKT signaling in rheumatoid arthritis fibroblasts; this DSCR9/RPLP2/PI3K/AKT axis mediates inflammation and hypercoagulability in RA.","method":"RNA pull-down assay, Western blot, RT-PCR, EdU assay, PI3K/AKT agonist rescue experiment","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA pull-down demonstrates DSCR9-RPLP2 interaction but mechanistic link to PI3K/AKT is based largely on pathway inhibitor/agonist experiments; single lab","pmids":["39376558"],"is_preprint":false}],"current_model":"RPLP2, as part of the ribosomal stalk complex with RPLP0 and RPLP1, promotes translation elongation through sequences encoding multiple transmembrane domains; it is selectively required for efficient translation of flaviviral and coronavirus mRNAs (interacting with viral 5'UTR via eIF4E), and outside its ribosomal role, RPLP2 can activate TLR4/PI3K/AKT/HIF-1α-driven aerobic glycolysis in cancer cells and is subject to post-transcriptional silencing via METTL14-mediated m6A modification read by YTHDC2."},"narrative":{"mechanistic_narrative":"RPLP2 is a ribosomal stalk protein that, together with RPLP0 and RPLP1, promotes translation elongation through challenging mRNA sequences, most notably those encoding multiple adjacent transmembrane domains where it relieves ribosome pausing during multi-pass membrane protein biogenesis [PMID:32890404]. This elongation function makes RPLP1/2 essential host factors for the replication of flaviviruses (DENV, YFV, ZIKV), whose structural polyproteins are TMD-rich [PMID:27974556, PMID:32890404]. RPLP2 also supports selective translation initiation of viral mRNAs: during coronavirus (PEDV) infection it is upregulated via phospho-eIF4E and engages the viral 5'UTR through association with eIF4E, recruiting the viral nucleocapsid protein into cap-bound complexes [PMID:36632964]. Beyond its ribosomal role, RPLP2 has been implicated in cancer cell metabolism and survival, where it activates TLR4/PI3K/AKT signaling to drive HIF-1α-dependent aerobic glycolysis in hepatocellular carcinoma [PMID:38052785] and sustains expression of the ferroptosis suppressor frataxin in diffuse large B-cell lymphoma [PMID:40564039]. RPLP2 mRNA is subject to METTL14-deposited m6A modification, read by YTHDC2, which destabilizes the transcript and suppresses RPLP2 expression in hepatocellular carcinoma [PMID:39955344].","teleology":[{"year":2017,"claim":"Established that the ribosomal stalk proteins RPLP1/2 are not merely structural but are selectively required host factors for flavivirus replication, linking them to viral protein synthesis.","evidence":"RNAi knockdown in A549 and HuH-7 cells with metabolic labeling and exogenous transgene reporter assays for DENV, YFV, ZIKV","pmids":["27974556"],"confidence":"High","gaps":["Did not resolve the precise step of translation affected","Mechanism distinguishing viral from cellular mRNA dependence unclear at this stage"]},{"year":2020,"claim":"Defined the molecular mechanism of RPLP1/2 action, showing they relieve ribosome pausing within sequences encoding multiple adjacent transmembrane domains, explaining both flaviviral dependence and a general role in multi-pass membrane protein biogenesis.","evidence":"Ribosome profiling in RPLP1/2-depleted cells plus DENV envelope protein stability and global translational analysis","pmids":["32890404"],"confidence":"High","gaps":["Structural basis for how the stalk senses TMD-encoding sequences not determined","Whether RPLP2 acts independently of RPLP1 not resolved"]},{"year":2023,"claim":"Extended RPLP2's pro-viral role to coronaviruses and to translation initiation, showing it bridges the viral 5'UTR and nucleocapsid protein to the cap-binding machinery via eIF4E.","evidence":"TMT proteomics, polysome profiling, RNA-binding protein immunoprecipitation and m7GTP cap pull-down during PEDV infection","pmids":["36632964"],"confidence":"Medium","gaps":["Direct RPLP2–eIF4E binding interface not mapped","Single lab; initiation role contrasts with the elongation role established for flaviviruses"]},{"year":2023,"claim":"Identified an extra-ribosomal function for RPLP2 in cancer metabolism, placing it upstream of TLR4/PI3K/AKT/HIF-1α signaling that drives aerobic glycolysis in hepatocellular carcinoma.","evidence":"siRNA knockdown with glycolytic enzyme/lactate readouts, PI3K/AKT inhibition and HIF-1α nuclear localization assays in HCC cells","pmids":["38052785"],"confidence":"Medium","gaps":["Direct RPLP2–TLR4 interaction not validated by binding assay","How a ribosomal protein reaches the cell surface for autocrine signaling unexplained"]},{"year":2025,"claim":"Showed RPLP2 expression is itself regulated post-transcriptionally, with METTL14-deposited m6A read by YTHDC2 destabilizing RPLP2 mRNA to suppress HCC progression.","evidence":"MeRIP, dual-luciferase reporter, RNA stability assays with METTL14 overexpression and RPLP2 knockdown in HCC cells","pmids":["39955344"],"confidence":"Medium","gaps":["Site-specific m6A residues on RPLP2 mRNA not mapped","Single lab; relationship to the TLR4/glycolysis axis not integrated"]},{"year":2025,"claim":"Linked RPLP2 to tumor cell survival via ferroptosis control, showing its depletion lowers frataxin and triggers ferroptosis in DLBCL.","evidence":"siRNA knockdown with lipid ROS/iron ferroptosis markers, proliferation assays and xenograft models in DLBCL","pmids":["40564039"],"confidence":"Medium","gaps":["Molecular link between RPLP2 and FXN expression not elucidated","Whether this reflects ribosomal or extra-ribosomal RPLP2 function unknown"]},{"year":2024,"claim":"Proposed an upstream regulator of RPLP2 in autoimmune disease, with lncRNA DSCR9 negatively regulating RPLP2 to control PI3K/AKT-driven inflammation in rheumatoid arthritis fibroblasts.","evidence":"RNA pull-down, Western blot, EdU assay and PI3K/AKT agonist rescue in RA fibroblasts","pmids":["39376558"],"confidence":"Low","gaps":["Mechanistic link to PI3K/AKT rests largely on pathway inhibitor/agonist experiments rather than direct interaction","DSCR9–RPLP2 regulation not confirmed by orthogonal methods","Single lab"]},{"year":null,"claim":"How RPLP2's canonical ribosomal stalk function mechanistically connects to its reported extra-ribosomal signaling roles (TLR4 activation, ferroptosis regulation) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical account of RPLP2 acting outside the ribosome","Direct binding partners in the signaling roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":["ribosomal stalk (RPLP0/RPLP1/RPLP2)"],"partners":["RPLP1","RPLP0","EIF4E"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05387","full_name":"Large ribosomal subunit protein P2","aliases":["60S acidic ribosomal protein P2","Renal carcinoma antigen NY-REN-44"],"length_aa":115,"mass_kda":11.7,"function":"Plays an important role in the elongation step of protein synthesis","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P05387/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPLP2","classification":"Common Essential","n_dependent_lines":1194,"n_total_lines":1208,"dependency_fraction":0.9884105960264901},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":10.0},{"gene":"DDX21","stoichiometry":10.0},{"gene":"ENY2","stoichiometry":10.0},{"gene":"G3BP1","stoichiometry":10.0},{"gene":"HMGB2","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}],"url":"https://opencell.sf.czbiohub.org/search/RPLP2","total_profiled":1310},"omim":[{"mim_id":"180530","title":"RIBOSOMAL PROTEIN LATERAL STALK SUBUNIT P2; RPLP2","url":"https://www.omim.org/entry/180530"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPLP2"},"hgnc":{"alias_symbol":["P2","RPP2","MGC71408","LP2"],"prev_symbol":["D11S2243E"]},"alphafold":{"accession":"P05387","domains":[{"cath_id":"1.10.10.1410","chopping":"1-65","consensus_level":"medium","plddt":86.8789,"start":1,"end":65}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05387","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05387-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05387-F1-predicted_aligned_error_v6.png","plddt_mean":67.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPLP2","jax_strain_url":"https://www.jax.org/strain/search?query=RPLP2"},"sequence":{"accession":"P05387","fasta_url":"https://rest.uniprot.org/uniprotkb/P05387.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05387/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05387"}},"corpus_meta":[{"pmid":"21040949","id":"PMC_21040949","title":"Expression of the ribosomal proteins Rplp0, Rplp1, and Rplp2 in gynecologic tumors.","date":"2010","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21040949","citation_count":75,"is_preprint":false},{"pmid":"27974556","id":"PMC_27974556","title":"RPLP1 and RPLP2 Are Essential Flavivirus Host Factors That Promote Early Viral Protein Accumulation.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/27974556","citation_count":66,"is_preprint":false},{"pmid":"8947466","id":"PMC_8947466","title":"LP2, a differentiation-associated lipid-binding protein expressed in bovine lens.","date":"1996","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8947466","citation_count":34,"is_preprint":false},{"pmid":"32890404","id":"PMC_32890404","title":"Ribosomal stalk proteins RPLP1 and RPLP2 promote biogenesis of flaviviral and cellular multi-pass transmembrane proteins.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32890404","citation_count":26,"is_preprint":false},{"pmid":"35903291","id":"PMC_35903291","title":"Lactobacillus plantarum Lp2 improved LPS-induced liver injury through the TLR-4/MAPK/NFκB and Nrf2-HO-1/CYP2E1 pathways in mice.","date":"2022","source":"Food & nutrition research","url":"https://pubmed.ncbi.nlm.nih.gov/35903291","citation_count":25,"is_preprint":false},{"pmid":"34618066","id":"PMC_34618066","title":"bHLH transcription factors LP1 and LP2 regulate longitudinal cell elongation.","date":"2021","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34618066","citation_count":23,"is_preprint":false},{"pmid":"19781006","id":"PMC_19781006","title":"The LP2 leucine-rich repeat receptor kinase gene promoter directs organ-specific, light-responsive expression in transgenic rice.","date":"2009","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/19781006","citation_count":23,"is_preprint":false},{"pmid":"36122811","id":"PMC_36122811","title":"Ameliorative effect of Lactobacillus plantarum Lp2 against cyclophosphamide-induced liver injury in mice.","date":"2022","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/36122811","citation_count":19,"is_preprint":false},{"pmid":"30822708","id":"PMC_30822708","title":"(2S)-N-2-methoxy-2-phenylethyl-6,7-benzomorphan compound (2S-LP2): Discovery of a biased mu/delta opioid receptor agonist.","date":"2019","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30822708","citation_count":18,"is_preprint":false},{"pmid":"38052785","id":"PMC_38052785","title":"RPLP2 activates TLR4 in an autocrine manner and promotes HIF-1α-induced metabolic reprogramming in hepatocellular carcinoma.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38052785","citation_count":15,"is_preprint":false},{"pmid":"34690781","id":"PMC_34690781","title":"The Multimodal MOPr/DOPr Agonist LP2 Reduces Allodynia in Chronic Constriction Injured Rats by Rescue of TGF-β1 Signalling.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34690781","citation_count":15,"is_preprint":false},{"pmid":"39376558","id":"PMC_39376558","title":"Regulating the lncRNA DSCR9/RPLP2/PI3K/AKT axis: an important mechanism of Xinfeng capsules in improving rheumatoid arthritis.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39376558","citation_count":14,"is_preprint":false},{"pmid":"26718464","id":"PMC_26718464","title":"Comparative Analysis of the Complete Genome of Lactobacillus plantarum GB-LP2 and Potential Candidate Genes for Host Immune System Enhancement.","date":"2016","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26718464","citation_count":12,"is_preprint":false},{"pmid":"34299443","id":"PMC_34299443","title":"LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34299443","citation_count":11,"is_preprint":false},{"pmid":"32985587","id":"PMC_32985587","title":"Inoculation of Ensifer fredii strain LP2/20 immobilized in agar results in growth promotion and alteration of bacterial community structure of Chinese kale planted soil.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32985587","citation_count":10,"is_preprint":false},{"pmid":"36632964","id":"PMC_36632964","title":"Proteomic screening identifies RPLp2 as a specific regulator for the translation of coronavirus.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36632964","citation_count":9,"is_preprint":false},{"pmid":"36493954","id":"PMC_36493954","title":"LP2, a cyclic angiotensin-(1-7) analog extended with an N-terminal D-lysine, impairs growth of patient-derived xenografts of colorectal carcinoma in mice.","date":"2022","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/36493954","citation_count":7,"is_preprint":false},{"pmid":"39955344","id":"PMC_39955344","title":"METTL14 suppresses the migration and invasion of hepatocellular carcinoma cells by m6A methylation of RPLP2.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39955344","citation_count":5,"is_preprint":false},{"pmid":"36813756","id":"PMC_36813756","title":"Design, synthesis, in vitro evaluation, and molecular modeling studies of N-substituted benzomorphans, analogs of LP2, as novel MOR ligands.","date":"2023","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/36813756","citation_count":5,"is_preprint":false},{"pmid":"32192416","id":"PMC_32192416","title":"Waste frying oil hydrolysis and lipase production by cold-adapted Pseudomonas yamanorum LP2 under non-sterile culture conditions.","date":"2020","source":"Environmental technology","url":"https://pubmed.ncbi.nlm.nih.gov/32192416","citation_count":5,"is_preprint":false},{"pmid":"37742799","id":"PMC_37742799","title":"AT2 receptor agonist LP2 restores respiratory function in a rat model of bleomycin-induced lung remodelling.","date":"2023","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/37742799","citation_count":2,"is_preprint":false},{"pmid":"36656652","id":"PMC_36656652","title":"LP2, a stable lanthipeptide derived from cAng-(1-7), exerts myeloprotective action in mice.","date":"2023","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/36656652","citation_count":2,"is_preprint":false},{"pmid":"40564039","id":"PMC_40564039","title":"Targeting RPLP2 Triggers DLBCL Ferroptosis by Decreasing FXN Expression.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40564039","citation_count":0,"is_preprint":false},{"pmid":"40895022","id":"PMC_40895022","title":"The simultaneous activation of μ- and δ-opioid receptors by (-)-2S-LP2 rescues allodynia with the contribution of TGF-β1 signaling in a rat chronic constriction injury model.","date":"2025","source":"Current research in pharmacology and drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40895022","citation_count":0,"is_preprint":false},{"pmid":"40744271","id":"PMC_40744271","title":"Proteomics reveals the role of the EamB transporter from Aeromonas hydrophila LP-2 in biofilm formation.","date":"2025","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/40744271","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15217,"output_tokens":2021,"usd":0.037983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8962,"output_tokens":2827,"usd":0.057743,"stage2_stop_reason":"end_turn"},"total_usd":0.095726,"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\": 2017,\n      \"finding\": \"RPLP1 and RPLP2 are essential host factors for flavivirus (DENV, YFV, ZIKV) replication; knockdown of RPLP1/2 strongly reduced early DENV protein accumulation and reduced DENV structural proteins expressed from an exogenous transgene, indicating a requirement for these ribosomal stalk proteins in viral translation elongation.\",\n      \"method\": \"RNA interference knockdown in A549 and HuH-7 cells, metabolic labeling of global protein synthesis, exogenous transgene reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi knockdown, metabolic labeling, transgene reporter), replicated across two human cell lines and in mosquitoes\",\n      \"pmids\": [\"27974556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RPLP1/2 function to relieve ribosome pausing within sequences encoding multiple adjacent transmembrane domains (TMDs) during translation elongation; ribosome profiling in RPLP1/2-depleted cells showed ribosomes pause in the DENV envelope coding sequence downstream of sequences encoding two adjacent TMDs, and depletion disproportionately affected ribosome density on cellular mRNAs encoding multiple TMDs, implicating RPLP1/2 in multi-pass transmembrane protein biogenesis.\",\n      \"method\": \"Ribosome profiling (Ribo-seq) in RPLP1/2-depleted cells, analysis of DENV envelope protein stability, global translational analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ribosome profiling provides genome-wide mechanistic resolution, combined with protein stability assays; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"32890404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RPLp2 promotes coronavirus (PEDV) mRNA translation in a p-eIF4E-dependent manner; PEDV infection upregulated RPLp2 translation via p-eIF4E, RPLp2 interacted with PEDV 5'UTR through association with eIF4E (shown by RNA binding protein immunoprecipitation), and the viral nucleocapsid protein was recruited into m7GTP-precipitated complexes (cap pull-down) with the assistance of RPLp2, supporting a role for RPLp2 in selective translation initiation of viral mRNA.\",\n      \"method\": \"TMT quantitative proteomics, bicistronic dual-reporter assay, polysome profiling, RNA binding protein immunoprecipitation, cap (m7GTP) pull-down assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (polysome profiling, RIP, cap pull-down) in a single lab\",\n      \"pmids\": [\"36632964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RPLP2 activates TLR4 on the surface of hepatocellular carcinoma (HCC) cells via autocrine signaling, which activates the downstream PI3K/AKT pathway, facilitating nuclear entry of HIF-1α and its transcriptional activation of glycolytic enzymes, thereby promoting aerobic glycolysis and HCC cell proliferation.\",\n      \"method\": \"siRNA knockdown of RPLP2, measurement of glycolytic enzyme expression and lactate production, PI3K/AKT pathway inhibition assays, HIF-1α nuclear localization experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — loss-of-function with pathway readouts, but single lab and mechanistic detail (direct TLR4 interaction) not fully validated by binding assay\",\n      \"pmids\": [\"38052785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL14 promotes m6A methylation of RPLP2 mRNA, reducing its stability and thereby suppressing RPLP2 expression in hepatocellular carcinoma; YTHDC2 acts as the m6A reader that decreases RPLP2 expression in this axis, and reduced RPLP2 inhibits HCC cell proliferation, migration, and invasion.\",\n      \"method\": \"Methylated RNA binding protein immunoprecipitation (MeRIP), dual-luciferase reporter assay, RNA stability determination, METTL14 overexpression and RPLP2 knockdown in HCC cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MeRIP establishes m6A modification on RPLP2 mRNA, RNA stability assay confirms functional consequence; single lab\",\n      \"pmids\": [\"39955344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPLP2 knockdown in diffuse large B-cell lymphoma (DLBCL) cells triggers ferroptosis by decreasing expression of the ferroptosis suppressor frataxin (FXN), establishing RPLP2 as a regulator of FXN-mediated ferroptosis in DLBCL.\",\n      \"method\": \"siRNA knockdown of RPLP2, lipid ROS and iron assays (ferroptosis markers), CCK8 and colony formation assays, xenograft mouse models\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — loss-of-function with specific ferroptosis readouts and in vivo validation; single lab, mechanism linking RPLP2 to FXN not fully elucidated at molecular level\",\n      \"pmids\": [\"40564039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"lncRNA DSCR9 negatively regulates RPLP2 expression (shown by RNA pull-down assay), and RPLP2 acts upstream of PI3K/AKT signaling in rheumatoid arthritis fibroblasts; this DSCR9/RPLP2/PI3K/AKT axis mediates inflammation and hypercoagulability in RA.\",\n      \"method\": \"RNA pull-down assay, Western blot, RT-PCR, EdU assay, PI3K/AKT agonist rescue experiment\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA pull-down demonstrates DSCR9-RPLP2 interaction but mechanistic link to PI3K/AKT is based largely on pathway inhibitor/agonist experiments; single lab\",\n      \"pmids\": [\"39376558\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPLP2, as part of the ribosomal stalk complex with RPLP0 and RPLP1, promotes translation elongation through sequences encoding multiple transmembrane domains; it is selectively required for efficient translation of flaviviral and coronavirus mRNAs (interacting with viral 5'UTR via eIF4E), and outside its ribosomal role, RPLP2 can activate TLR4/PI3K/AKT/HIF-1α-driven aerobic glycolysis in cancer cells and is subject to post-transcriptional silencing via METTL14-mediated m6A modification read by YTHDC2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RPLP2 is a ribosomal stalk protein that, together with RPLP0 and RPLP1, promotes translation elongation through challenging mRNA sequences, most notably those encoding multiple adjacent transmembrane domains where it relieves ribosome pausing during multi-pass membrane protein biogenesis [#1]. This elongation function makes RPLP1/2 essential host factors for the replication of flaviviruses (DENV, YFV, ZIKV), whose structural polyproteins are TMD-rich [#0, #1]. RPLP2 also supports selective translation initiation of viral mRNAs: during coronavirus (PEDV) infection it is upregulated via phospho-eIF4E and engages the viral 5'UTR through association with eIF4E, recruiting the viral nucleocapsid protein into cap-bound complexes [#2]. Beyond its ribosomal role, RPLP2 has been implicated in cancer cell metabolism and survival, where it activates TLR4/PI3K/AKT signaling to drive HIF-1\\u03b1-dependent aerobic glycolysis in hepatocellular carcinoma [#3] and sustains expression of the ferroptosis suppressor frataxin in diffuse large B-cell lymphoma [#5]. RPLP2 mRNA is subject to METTL14-deposited m6A modification, read by YTHDC2, which destabilizes the transcript and suppresses RPLP2 expression in hepatocellular carcinoma [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that the ribosomal stalk proteins RPLP1/2 are not merely structural but are selectively required host factors for flavivirus replication, linking them to viral protein synthesis.\",\n      \"evidence\": \"RNAi knockdown in A549 and HuH-7 cells with metabolic labeling and exogenous transgene reporter assays for DENV, YFV, ZIKV\",\n      \"pmids\": [\"27974556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve the precise step of translation affected\",\n        \"Mechanism distinguishing viral from cellular mRNA dependence unclear at this stage\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the molecular mechanism of RPLP1/2 action, showing they relieve ribosome pausing within sequences encoding multiple adjacent transmembrane domains, explaining both flaviviral dependence and a general role in multi-pass membrane protein biogenesis.\",\n      \"evidence\": \"Ribosome profiling in RPLP1/2-depleted cells plus DENV envelope protein stability and global translational analysis\",\n      \"pmids\": [\"32890404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how the stalk senses TMD-encoding sequences not determined\",\n        \"Whether RPLP2 acts independently of RPLP1 not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended RPLP2's pro-viral role to coronaviruses and to translation initiation, showing it bridges the viral 5'UTR and nucleocapsid protein to the cap-binding machinery via eIF4E.\",\n      \"evidence\": \"TMT proteomics, polysome profiling, RNA-binding protein immunoprecipitation and m7GTP cap pull-down during PEDV infection\",\n      \"pmids\": [\"36632964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct RPLP2\\u2013eIF4E binding interface not mapped\",\n        \"Single lab; initiation role contrasts with the elongation role established for flaviviruses\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an extra-ribosomal function for RPLP2 in cancer metabolism, placing it upstream of TLR4/PI3K/AKT/HIF-1\\u03b1 signaling that drives aerobic glycolysis in hepatocellular carcinoma.\",\n      \"evidence\": \"siRNA knockdown with glycolytic enzyme/lactate readouts, PI3K/AKT inhibition and HIF-1\\u03b1 nuclear localization assays in HCC cells\",\n      \"pmids\": [\"38052785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct RPLP2\\u2013TLR4 interaction not validated by binding assay\",\n        \"How a ribosomal protein reaches the cell surface for autocrine signaling unexplained\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed RPLP2 expression is itself regulated post-transcriptionally, with METTL14-deposited m6A read by YTHDC2 destabilizing RPLP2 mRNA to suppress HCC progression.\",\n      \"evidence\": \"MeRIP, dual-luciferase reporter, RNA stability assays with METTL14 overexpression and RPLP2 knockdown in HCC cells\",\n      \"pmids\": [\"39955344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Site-specific m6A residues on RPLP2 mRNA not mapped\",\n        \"Single lab; relationship to the TLR4/glycolysis axis not integrated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked RPLP2 to tumor cell survival via ferroptosis control, showing its depletion lowers frataxin and triggers ferroptosis in DLBCL.\",\n      \"evidence\": \"siRNA knockdown with lipid ROS/iron ferroptosis markers, proliferation assays and xenograft models in DLBCL\",\n      \"pmids\": [\"40564039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular link between RPLP2 and FXN expression not elucidated\",\n        \"Whether this reflects ribosomal or extra-ribosomal RPLP2 function unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed an upstream regulator of RPLP2 in autoimmune disease, with lncRNA DSCR9 negatively regulating RPLP2 to control PI3K/AKT-driven inflammation in rheumatoid arthritis fibroblasts.\",\n      \"evidence\": \"RNA pull-down, Western blot, EdU assay and PI3K/AKT agonist rescue in RA fibroblasts\",\n      \"pmids\": [\"39376558\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanistic link to PI3K/AKT rests largely on pathway inhibitor/agonist experiments rather than direct interaction\",\n        \"DSCR9\\u2013RPLP2 regulation not confirmed by orthogonal methods\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RPLP2's canonical ribosomal stalk function mechanistically connects to its reported extra-ribosomal signaling roles (TLR4 activation, ferroptosis regulation) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical account of RPLP2 acting outside the ribosome\",\n        \"Direct binding partners in the signaling roles not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"ribosomal stalk (RPLP0/RPLP1/RPLP2)\"],\n    \"partners\": [\"RPLP1\", \"RPLP0\", \"EIF4E\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}