{"gene":"RPL13A","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2012,"finding":"GAPDH functions as a chaperone that shields newly released (extraribosomal) RPL13A from proteasomal degradation. Following IFN-γ-induced release from ribosomes, L13a assembles into the GAIT complex for translational control of inflammation-related mRNAs. GAPDH protective activity is lost upon S-nitrosylation at Cys247 (induced by oxidized LDL + IFN-γ), causing proteasomal degradation of essentially the entire cellular complement of L13a and defective GAIT-mediated translational control.","method":"Co-immunoprecipitation of GAPDH–L13a complex; proteasome inhibitor rescue assays; site-directed mutagenesis of GAPDH Cys247; S-nitrosylation detection; translational reporter assays in cells treated with oxLDL and IFN-γ","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of specific residue, multiple orthogonal functional assays (proteasome inhibition, translational reporters), mechanistic chain from PTM to phenotype established in single rigorous study","pmids":["22771119"],"is_preprint":false},{"year":1999,"finding":"The human RPL13A gene (encoding ribosomal protein L13a/uL13) and the adjacent RPS11 gene are tandemly organized in both human and mouse genomes. Four snoRNA genes (U32, U33, U34, U35) are encoded within the introns of RPL13A (introns 2, 4, 5, and 6), establishing the genomic architecture of the locus and the co-localization of these intronic non-coding RNAs with the protein-coding gene.","method":"Genomic sequencing, gene structure determination, and sequence comparison of human and mouse RPL13A/Rpl13a loci","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic sequencing with comparative analysis establishes locus architecture; single lab, one method but definitive structural finding","pmids":["10580157"],"is_preprint":false},{"year":2025,"finding":"Free (ribosome-released) RPL13A (uL13) is ADP-ribosylated (PARylated) by PARP1 and PARP2 in vitro; this modification does not occur on ribosome-bound RPL13A. RPL13A is identified as one of the major targets of PARylation among 60S ribosomal proteins, and the modification is enhanced by HPF1, which also switches the modification preferentially to serine/tyrosine residues.","method":"In vitro ADP-ribosylation assays with radioactively labeled NAD+ using isolated ribosomal subunits and total ribosomal proteins; comparison of ribosome-bound vs. free RPs; HPF1 co-factor assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution assay with defined components, but preprint, single lab, no cellular validation of the modification","pmids":["bio_10.1101_2025.09.15.676193"],"is_preprint":true}],"current_model":"RPL13A (uL13) functions both as a structural component of the 60S ribosomal subunit and as an extraribosomal regulator: upon IFN-γ stimulation it is released from ribosomes and assembles into the GAIT complex to translationally silence inflammation-related mRNAs; in this extraribosomal state it is protected from proteasomal degradation by GAPDH acting as a chaperone, a protection lost when GAPDH is S-nitrosylated at Cys247, and free RPL13A is also a substrate for PARP1/PARP2-mediated ADP-ribosylation in vitro. The RPL13A genomic locus additionally encodes four intronic snoRNAs (U32–U35) that regulate cellular ROS and metabolism independently of the RPL13A protein."},"narrative":{"mechanistic_narrative":"RPL13A (uL13) is a 60S ribosomal protein that doubles as an extraribosomal regulator of inflammatory gene expression: following IFN-γ stimulation it is released from ribosomes and assembles into the GAIT complex to translationally silence inflammation-related mRNAs [PMID:22771119]. In its free, ribosome-released state RPL13A is stabilized by GAPDH, which acts as a chaperone shielding it from proteasomal degradation; this protection is abolished when GAPDH is S-nitrosylated at Cys247 (induced by oxidized LDL plus IFN-γ), leading to degradation of essentially the entire cellular pool of L13a and loss of GAIT-mediated translational control [PMID:22771119]. The RPL13A genomic locus is tandemly organized with RPS11 and harbors four intronic snoRNAs (U32–U35) within introns 2, 4, 5, and 6, co-localizing these non-coding RNAs with the protein-coding gene [PMID:10580157]. Free RPL13A is additionally a substrate for PARP1/PARP2-mediated ADP-ribosylation in vitro, a modification absent on ribosome-bound RPL13A [PMID:bio_10.1101_2025.09.15.676193].","teleology":[{"year":1999,"claim":"Establishing the architecture of the RPL13A locus revealed it is not a simple protein-coding gene but a host for four intronic snoRNAs co-localized with the coding sequence, framing the locus as a multi-output genetic unit.","evidence":"Genomic sequencing and comparative human/mouse analysis of the RPL13A/RPS11 region","pmids":["10580157"],"confidence":"Medium","gaps":["Does not assign function to the intronic snoRNAs U32–U35","Does not establish whether snoRNA biogenesis depends on RPL13A transcription or splicing","No link between locus architecture and the extraribosomal protein function"]},{"year":2012,"claim":"Connecting RPL13A stability to a redox-sensitive chaperone resolved how the extraribosomal GAIT-forming pool of L13a is maintained and how it is dismantled, linking a specific GAPDH post-translational modification to defective translational control of inflammation.","evidence":"Co-immunoprecipitation of the GAPDH–L13a complex, proteasome-inhibitor rescue, GAPDH Cys247 site-directed mutagenesis, S-nitrosylation detection, and translational reporter assays under oxLDL/IFN-γ","pmids":["22771119"],"confidence":"High","gaps":["Does not define the structural basis of GAPDH–L13a recognition","Does not identify the E3 ligase or degron driving proteasomal turnover of free L13a","Does not establish how release from the ribosome is itself triggered"]},{"year":2025,"claim":"Identifying free RPL13A as a major PARylation target among 60S proteins introduced a candidate post-translational layer distinguishing the ribosome-bound from the extraribosomal state, since the modification occurs only on released protein.","evidence":"In vitro ADP-ribosylation assays with radiolabeled NAD+ on isolated subunits and total ribosomal proteins, comparing bound versus free RPs, with HPF1 co-factor titration (preprint)","pmids":["bio_10.1101_2025.09.15.676193"],"confidence":"Low","gaps":["In vitro reconstitution only; the modification is not validated in cells","Functional consequence of PARylation for GAIT assembly or L13a stability is unknown","Modified residues are not mapped beyond a serine/tyrosine preference conferred by HPF1"]},{"year":null,"claim":"How the multiple post-translational and chaperone inputs (GAPDH protection, S-nitrosylation-triggered degradation, PARylation) are integrated to govern the balance between ribosomal and GAIT-bound RPL13A remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model coupling ribosome release, PARylation, and GAPDH-dependent stability","Relationship between the intronic snoRNA outputs and protein-level regulation is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]}],"complexes":["GAIT complex","60S ribosomal subunit"],"partners":["GAPDH","PARP1","PARP2","HPF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P40429","full_name":"Large ribosomal subunit protein uL13","aliases":["23 kDa highly basic protein","60S ribosomal protein L13a"],"length_aa":203,"mass_kda":23.6,"function":"Associated with ribosomes but is not required for canonical ribosome function and has extra-ribosomal functions (PubMed:14567916, PubMed:17218275, PubMed:23636399, PubMed:32669547). Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes (PubMed:23071094). Upon interferon-gamma activation and subsequent phosphorylation dissociates from the ribosome and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation (PubMed:23071094). In the GAIT complex interacts with m7G cap-bound eIF4G at or near the eIF3-binding site and blocks the recruitment of the 43S ribosomal complex (PubMed:23071094). Involved in methylation of rRNA (PubMed:17921318)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P40429/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL13A","classification":"Common Essential","n_dependent_lines":383,"n_total_lines":383,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RPL13A","total_profiled":1310},"omim":[{"mim_id":"619225","title":"RIBOSOMAL PROTEIN L13A; RPL13A","url":"https://www.omim.org/entry/619225"},{"mim_id":"610173","title":"MICRO RNA 10A; MIR10A","url":"https://www.omim.org/entry/610173"},{"mim_id":"603658","title":"RIBOSOMAL PROTEIN S7; RPS7","url":"https://www.omim.org/entry/603658"},{"mim_id":"603289","title":"DEATH-ASSOCIATED PROTEIN KINASE 3; DAPK3","url":"https://www.omim.org/entry/603289"},{"mim_id":"600831","title":"DEATH-ASSOCIATED PROTEIN KINASE 1; DAPK1","url":"https://www.omim.org/entry/600831"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPL13A"},"hgnc":{"alias_symbol":["L13A","uL13"],"prev_symbol":["TSTA1"]},"alphafold":{"accession":"P40429","domains":[{"cath_id":"3.90.1180.10","chopping":"6-147","consensus_level":"high","plddt":97.2915,"start":6,"end":147},{"cath_id":"1.20.5","chopping":"149-203","consensus_level":"medium","plddt":95.4785,"start":149,"end":203}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P40429","model_url":"https://alphafold.ebi.ac.uk/files/AF-P40429-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P40429-F1-predicted_aligned_error_v6.png","plddt_mean":95.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPL13A","jax_strain_url":"https://www.jax.org/strain/search?query=RPL13A"},"sequence":{"accession":"P40429","fasta_url":"https://rest.uniprot.org/uniprotkb/P40429.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P40429/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P40429"}},"corpus_meta":[{"pmid":"8393574","id":"PMC_8393574","title":"Processing 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kinase.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24574411","citation_count":12,"is_preprint":false},{"pmid":"9764560","id":"PMC_9764560","title":"Evaluation of restriction fragment length polymorphism analysis of the UL10-UL13 genomic region for rapid identification of human cytomegalovirus strains.","date":"1998","source":"European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9764560","citation_count":9,"is_preprint":false},{"pmid":"36531988","id":"PMC_36531988","title":"Mechanism of herpesvirus protein kinase UL13 in immune escape and viral replication.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36531988","citation_count":8,"is_preprint":false},{"pmid":"19531264","id":"PMC_19531264","title":"Improved long-term expression from helper virus-free HSV-1 vectors packaged using combinations of mutated HSV-1 proteins that include the UL13 protein kinase and specific components of the VP16 transcriptional complex.","date":"2009","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19531264","citation_count":7,"is_preprint":false},{"pmid":"23065125","id":"PMC_23065125","title":"Transcription characteristics of the human cytomegalovirus UL13 gene.","date":"2012","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23065125","citation_count":4,"is_preprint":false},{"pmid":"39938620","id":"PMC_39938620","title":"Rpl13a snoRNAs-regulated NADPH oxidase 1-dependent ROS generation: A novel RBC pathway mediating complement C3a deposition and triggering thrombosis in aging and venous blood clotting disorders.","date":"2025","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39938620","citation_count":4,"is_preprint":false},{"pmid":"28192165","id":"PMC_28192165","title":"Copy-number variation of housekeeping gene rpl13a in rat strains selected for nervous system excitability.","date":"2017","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/28192165","citation_count":4,"is_preprint":false},{"pmid":"36993506","id":"PMC_36993506","title":"DISTINCT ROLES OF VIRAL US3 AND UL13 PROTEIN KINASES IN HERPES VIRUS SIMPLEX TYPE 1 (HSV-1) NUCLEAR EGRESS.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36993506","citation_count":3,"is_preprint":false},{"pmid":"38235617","id":"PMC_38235617","title":"Vertical mother-to-infant transmission of herpes simplex virus 2 is correlated with tropism due to mutations in viral UL13.","date":"2024","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/38235617","citation_count":3,"is_preprint":false},{"pmid":"40058703","id":"PMC_40058703","title":"Red blood cell Rpl13a small noncoding nucleolar RNAs guides 2'-O-methylation on peroxidasin messenger RNA promoting venous thrombosis in aging.","date":"2025","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/40058703","citation_count":3,"is_preprint":false},{"pmid":"33357689","id":"PMC_33357689","title":"Two nuclear localization signals regulate intracellular localization of the duck enteritis virus UL13 protein.","date":"2020","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/33357689","citation_count":2,"is_preprint":false},{"pmid":"40371475","id":"PMC_40371475","title":"Rpl13a snoRNAs U34 and U35a: New Targets for Sickle Cell Disease Complications.","date":"2025","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/40371475","citation_count":1,"is_preprint":false},{"pmid":"41025809","id":"PMC_41025809","title":"Identification of viral activators of the HSV-2 UL13 protein kinase.","date":"2025","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/41025809","citation_count":1,"is_preprint":false},{"pmid":"40652815","id":"PMC_40652815","title":"Human cytomegalovirus protein UL13 targets to mitochondria to induce cuproptosis.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/40652815","citation_count":1,"is_preprint":false},{"pmid":"39243656","id":"PMC_39243656","title":"Pseudorabies virus UL13 primes inflammatory response through downregulating heat shock factor 1.","date":"2024","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/39243656","citation_count":1,"is_preprint":false},{"pmid":"40935035","id":"PMC_40935035","title":"Duck plague virus UL13 hijacks an RNA-binding protein, interferon induced protein with tetratricopeptide repeats 5, to promote replication.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40935035","citation_count":1,"is_preprint":false},{"pmid":"40777413","id":"PMC_40777413","title":"Rpl13a snoRNAs Downregulate Smooth Muscle Cell COX4I2 and Promote Neointimal Hyperplasia.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40777413","citation_count":0,"is_preprint":false},{"pmid":"19445169","id":"PMC_19445169","title":"[Kinase domain analysis of MDV-1 CVI988/Rispens UL13 and preferred codon fragments expression in Escherichia coli].","date":"2009","source":"Wei sheng wu xue bao = Acta microbiologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/19445169","citation_count":0,"is_preprint":false},{"pmid":"42227596","id":"PMC_42227596","title":"METTL14-Mediated RPL13A Expression Regulates Apoptosis and Invasion of Osteosarcoma via the PTEN/PI3K/AKT Signaling Pathway.","date":"2026","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/42227596","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.15.676193","title":"Interplay between human ribosomal proteins, PARP1, PARP2, HPF1 and histones","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.15.676193","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.23.666475","title":"<i>Rpl13a</i>  snoRNAs Downregulate Smooth Muscle Cell COX4I2 and Promote Neointimal Hyperplasia","date":"2025-07-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.23.666475","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.22.677736","title":"Stable reference genes for 24-hour circadian profiling of core clock genes in the blood of obstructive sleep apnea patients","date":"2025-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677736","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.24.25340856","title":"Development of Diagnostic Real-Time Reverse Transcription-PCR Assays for SARS-CoV-2 using Polyvinyl Alcohol (PVA) Sponge as Saliva Collection Tool","date":"2025-11-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.24.25340856","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.28.645676","title":"Alternative splicing generates a Ribosomal Protein S24 isoform induced by neuroinflammation and neurodegeneration","date":"2025-04-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.28.645676","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.07.642051","title":"Single-Cell and WGCNA Integrative Analysis Reveal the Key Chondrocytes Niches and Pathogenic Genes in Intervertebral Disc Degeneration","date":"2025-03-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.07.642051","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.06.25327057","title":"Identification of (ultra-)rare functional promoter mutations in cancer using sequence-based deep learning models","date":"2025-05-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.06.25327057","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.02.626357","title":"RNA Binding of GAPDH Controls Transcript Stability and Protein Translation in Acute Myeloid Leukemia","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.02.626357","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39725,"output_tokens":1602,"usd":0.071602,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7622,"output_tokens":1754,"usd":0.04098,"stage2_stop_reason":"end_turn"},"total_usd":0.112582,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to classify each paper carefully. The query gene is **RPL13A** (human ribosomal protein L13a, also known as uL13/TSTA1). The vast majority of papers in this corpus are about **herpesvirus UL13 protein kinase** — a completely different gene that shares the \"UL13\" symbol. These are symbol collisions and must be excluded.\n\nPapers about the canonical RPL13A protein:\n- PMID 22771119: GAPDH as chaperone protecting L13a\n- PMID 27820699: Rpl13a snoRNAs (non-protein products — EXCLUDE as non-protein locus products)\n- PMID 10580157: Gene organization/structure of RPL13A locus\n- PMID 20716364, 25523336, 27304673: Reference gene stability studies — no mechanistic findings\n- PMID 39938620, 40058703, 40371475: snoRNA studies — non-protein products, EXCLUDE\n- bio_10.1101_2025.09.15.676193: RPL13A ADP-ribosylation by PARP1/PARP2\n- PMID 28192165: CNV study, no mechanism\n- PMID 42227596: METTL14/RPL13a/PTEN — m6A modification of RPL13A mRNA (epigenetic regulation of expression)\n- bio_10.1101_2024.12.02.626357: GAPDH binds RPL13a mRNA — about RNA, not protein mechanism\n- PMID 36531988: Review of UL13 kinase — herpesvirus, EXCLUDE\n\nFor RPL13A protein specifically, the key mechanistic paper is PMID 22771119 (GAPDH chaperone for extraribosomal L13a) and the preprint about PARP1/2 ADP-ribosylation.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"GAPDH functions as a chaperone that shields newly released (extraribosomal) RPL13A from proteasomal degradation. Following IFN-γ-induced release from ribosomes, L13a assembles into the GAIT complex for translational control of inflammation-related mRNAs. GAPDH protective activity is lost upon S-nitrosylation at Cys247 (induced by oxidized LDL + IFN-γ), causing proteasomal degradation of essentially the entire cellular complement of L13a and defective GAIT-mediated translational control.\",\n      \"method\": \"Co-immunoprecipitation of GAPDH–L13a complex; proteasome inhibitor rescue assays; site-directed mutagenesis of GAPDH Cys247; S-nitrosylation detection; translational reporter assays in cells treated with oxLDL and IFN-γ\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of specific residue, multiple orthogonal functional assays (proteasome inhibition, translational reporters), mechanistic chain from PTM to phenotype established in single rigorous study\",\n      \"pmids\": [\"22771119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human RPL13A gene (encoding ribosomal protein L13a/uL13) and the adjacent RPS11 gene are tandemly organized in both human and mouse genomes. Four snoRNA genes (U32, U33, U34, U35) are encoded within the introns of RPL13A (introns 2, 4, 5, and 6), establishing the genomic architecture of the locus and the co-localization of these intronic non-coding RNAs with the protein-coding gene.\",\n      \"method\": \"Genomic sequencing, gene structure determination, and sequence comparison of human and mouse RPL13A/Rpl13a loci\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic sequencing with comparative analysis establishes locus architecture; single lab, one method but definitive structural finding\",\n      \"pmids\": [\"10580157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Free (ribosome-released) RPL13A (uL13) is ADP-ribosylated (PARylated) by PARP1 and PARP2 in vitro; this modification does not occur on ribosome-bound RPL13A. RPL13A is identified as one of the major targets of PARylation among 60S ribosomal proteins, and the modification is enhanced by HPF1, which also switches the modification preferentially to serine/tyrosine residues.\",\n      \"method\": \"In vitro ADP-ribosylation assays with radioactively labeled NAD+ using isolated ribosomal subunits and total ribosomal proteins; comparison of ribosome-bound vs. free RPs; HPF1 co-factor assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution assay with defined components, but preprint, single lab, no cellular validation of the modification\",\n      \"pmids\": [\"bio_10.1101_2025.09.15.676193\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPL13A (uL13) functions both as a structural component of the 60S ribosomal subunit and as an extraribosomal regulator: upon IFN-γ stimulation it is released from ribosomes and assembles into the GAIT complex to translationally silence inflammation-related mRNAs; in this extraribosomal state it is protected from proteasomal degradation by GAPDH acting as a chaperone, a protection lost when GAPDH is S-nitrosylated at Cys247, and free RPL13A is also a substrate for PARP1/PARP2-mediated ADP-ribosylation in vitro. The RPL13A genomic locus additionally encodes four intronic snoRNAs (U32–U35) that regulate cellular ROS and metabolism independently of the RPL13A protein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL13A (uL13) is a 60S ribosomal protein that doubles as an extraribosomal regulator of inflammatory gene expression: following IFN-γ stimulation it is released from ribosomes and assembles into the GAIT complex to translationally silence inflammation-related mRNAs [#0]. In its free, ribosome-released state RPL13A is stabilized by GAPDH, which acts as a chaperone shielding it from proteasomal degradation; this protection is abolished when GAPDH is S-nitrosylated at Cys247 (induced by oxidized LDL plus IFN-γ), leading to degradation of essentially the entire cellular pool of L13a and loss of GAIT-mediated translational control [#0]. The RPL13A genomic locus is tandemly organized with RPS11 and harbors four intronic snoRNAs (U32–U35) within introns 2, 4, 5, and 6, co-localizing these non-coding RNAs with the protein-coding gene [#1]. Free RPL13A is additionally a substrate for PARP1/PARP2-mediated ADP-ribosylation in vitro, a modification absent on ribosome-bound RPL13A [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the architecture of the RPL13A locus revealed it is not a simple protein-coding gene but a host for four intronic snoRNAs co-localized with the coding sequence, framing the locus as a multi-output genetic unit.\",\n      \"evidence\": \"Genomic sequencing and comparative human/mouse analysis of the RPL13A/RPS11 region\",\n      \"pmids\": [\"10580157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not assign function to the intronic snoRNAs U32–U35\",\n        \"Does not establish whether snoRNA biogenesis depends on RPL13A transcription or splicing\",\n        \"No link between locus architecture and the extraribosomal protein function\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connecting RPL13A stability to a redox-sensitive chaperone resolved how the extraribosomal GAIT-forming pool of L13a is maintained and how it is dismantled, linking a specific GAPDH post-translational modification to defective translational control of inflammation.\",\n      \"evidence\": \"Co-immunoprecipitation of the GAPDH–L13a complex, proteasome-inhibitor rescue, GAPDH Cys247 site-directed mutagenesis, S-nitrosylation detection, and translational reporter assays under oxLDL/IFN-γ\",\n      \"pmids\": [\"22771119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not define the structural basis of GAPDH–L13a recognition\",\n        \"Does not identify the E3 ligase or degron driving proteasomal turnover of free L13a\",\n        \"Does not establish how release from the ribosome is itself triggered\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying free RPL13A as a major PARylation target among 60S proteins introduced a candidate post-translational layer distinguishing the ribosome-bound from the extraribosomal state, since the modification occurs only on released protein.\",\n      \"evidence\": \"In vitro ADP-ribosylation assays with radiolabeled NAD+ on isolated subunits and total ribosomal proteins, comparing bound versus free RPs, with HPF1 co-factor titration (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.15.676193\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"In vitro reconstitution only; the modification is not validated in cells\",\n        \"Functional consequence of PARylation for GAIT assembly or L13a stability is unknown\",\n        \"Modified residues are not mapped beyond a serine/tyrosine preference conferred by HPF1\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple post-translational and chaperone inputs (GAPDH protection, S-nitrosylation-triggered degradation, PARylation) are integrated to govern the balance between ribosomal and GAIT-bound RPL13A remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unified model coupling ribosome release, PARylation, and GAPDH-dependent stability\",\n        \"Relationship between the intronic snoRNA outputs and protein-level regulation is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"GAIT complex\", \"60S ribosomal subunit\"],\n    \"partners\": [\"GAPDH\", \"PARP1\", \"PARP2\", \"HPF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}