{"gene":"RRBP1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2013,"finding":"RRBP1 knockdown by shRNA in lung cancer cells caused ER stress, reduced cell viability and tumorigenicity, and significantly decreased GRP78 protein expression. Ectopic overexpression of RRBP1 alleviated apoptosis induced by ER stress agents (tunicamycin, 2-deoxy-D-glucose, doxorubicin) by enhancing GRP78 protein expression, and RRBP1 was implicated in regulating mRNA stability of UPR components including ATF6 and GRP78.","method":"shRNA knockdown, ectopic overexpression, cell viability assays, immunohistochemistry, bioinformatic correlation (GSE10072)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype plus gain-of-function rescue, single lab, two orthogonal approaches (KD + OE), but no direct biochemical reconstitution of RRBP1-GRP78 mechanism","pmids":["23318453"],"is_preprint":false},{"year":2016,"finding":"A novel recurrent RRBP1-ALK gene fusion was identified in epithelioid inflammatory myofibroblastic sarcoma. The RRBP1-ALK fusion produced constitutively activated ALK oncoprotein with cytoplasmic/perinuclear ALK localization (distinct from nuclear membranous localization seen with RANBP2-ALK fusions), identified by ALK immunoprecipitation followed by mass spectrometry.","method":"ALK immunoprecipitation, mass spectrometry, FISH, immunohistochemistry","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — protein purification plus mass spectrometry identification, replicated in multiple independent tumor cases (3 EIMS cases with RRBP1-ALK confirmed), multiple orthogonal methods","pmids":["27874193"],"is_preprint":false},{"year":2022,"finding":"During mitochondrial protein import stress (MPIS), cytosol-retained NLRX1 recruits RRBP1 (a ribosome-binding transmembrane protein of the ER) which relocates to the mitochondrial vicinity. The NLRX1/RRBP1 complex controls LC3 recruitment and lipidation at the site of mitophagosome formation, independently of canonical PINK1 signaling. RRBP1 interaction with NLRX1 was demonstrated and RRBP1 relocation to mitochondrial vicinity during MPIS was documented.","method":"Co-immunoprecipitation, subcellular fractionation/live imaging of RRBP1 relocalization, genetic loss-of-function (NLRX1 KO, RRBP1 depletion), LC3 lipidation assays, in vivo skeletal muscle mitophagy assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing NLRX1/RRBP1 complex, direct localization experiment with functional consequence, multiple genetic models (KO, depletion), in vivo validation, single rigorous study with multiple orthogonal methods","pmids":["35752171"],"is_preprint":false},{"year":2021,"finding":"USP35 (a deubiquitinating enzyme) directly interacts with RRBP1 and prevents its proteasomal degradation by deubiquitination, thereby stabilizing RRBP1. Functionally, USP35 alleviates ER stress-induced apoptosis in non-small cell lung cancer cells through this stabilization of RRBP1.","method":"iTRAQ comparative proteomics, Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, genetic KD/OE, cell apoptosis assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction verified by Co-IP, proteasomal degradation demonstrated, functional rescue experiment, single lab","pmids":["34618999"],"is_preprint":false},{"year":2024,"finding":"P180/RRBP1 functions as an axonally distributed ribosome receptor in developing rat hippocampal neurons. RRBP1 regulates local mRNA translation on axonal ER tubules and binds to mRNAs enriched for axonal membrane proteins. Impairment of axonal ER-ribosome interactions via RRBP1 disruption causes defects in axon morphology, demonstrating that RRBP1-mediated ER-ribosome contacts are required for proper axon development.","method":"Nanoscale resolution imaging, ribosome contact mapping, RRBP1 loss-of-function, mRNA binding assays, axon morphology readouts, live neuron imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with functional consequence, mRNA binding demonstrated, loss-of-function with defined morphological phenotype, nanoscale imaging providing structural resolution, single rigorous study with multiple orthogonal methods","pmids":["38815583"],"is_preprint":false},{"year":2012,"finding":"RRBP1 protein is overexpressed in 84% of breast carcinoma cases. Subcellular localization of RRBP1 was predominantly cytoplasmic with intense perinuclear staining, consistent with its ER membrane localization.","method":"Immunohistochemical labeling of tissue microarrays (219 breast carcinoma cases), integration with public gene expression databases","journal":"Clinical proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — IHC-based subcellular localization with no functional follow-up, single method, no mechanistic experiment","pmids":["22709790"],"is_preprint":false},{"year":2021,"finding":"RRBP1 regulates YAP1 (Yes-associated protein 1), a key effector of the Hippo pathway, to induce cisplatin resistance in oral squamous cell carcinoma. Genetic knockout or pharmacological inhibition (Radezolid) of RRBP1 restored cisplatin-mediated cell death in chemoresistant OSCC cells and reduced tumor burden in PDC xenografts.","method":"RNA sequencing, global proteomic profiling, RRBP1 knockout, pharmacological inhibition, PDC xenograft experiments, YAP1 expression analysis","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular target (YAP1) and functional phenotype, in vivo xenograft validation, single lab with multiple orthogonal approaches","pmids":["33762722"],"is_preprint":false},{"year":2016,"finding":"The 5' UTR of RRBP1 mRNA contains an internal ribosome entry site (IRES). La autoantigen binds to the RRBP1 IRES element and facilitates cap-independent translation initiation under cellular stress conditions (chemotherapeutic drug treatment or serum starvation). Two apical GARR loops within the IRES are important for La binding. The core IRES activity was mapped to nucleotides -237 to -58.","method":"IRES reporter assays, RNA pulldown/binding assays, deletion mapping, La overexpression and knockdown, stress induction experiments in hepatocellular carcinoma cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein binding assay plus functional IRES reporter with deletion mapping, single lab, multiple orthogonal approaches","pmids":["27447629"],"is_preprint":false}],"current_model":"RRBP1 (ribosome-binding protein 1/P180) is an ER transmembrane ribosome receptor that anchors ribosomes to the rough ER membrane; it regulates local mRNA translation at axonal ER tubules (binding mRNAs for membrane proteins), forms a complex with NLRX1 to control LC3 lipidation and mitophagosome formation in response to mitochondrial protein import stress, is stabilized by the deubiquitinase USP35 to protect against ER stress-induced apoptosis, promotes cancer cell survival by enhancing GRP78 expression and by regulating the Hippo effector YAP1 to drive chemoresistance, and can be translocated as a fusion oncoprotein (RRBP1-ALK) driving constitutive ALK kinase activity in epithelioid inflammatory myofibroblastic sarcoma."},"narrative":{"mechanistic_narrative":"RRBP1 (P180) is an endoplasmic reticulum transmembrane ribosome receptor that anchors ribosomes to the ER membrane and organizes local, compartmentalized translation [PMID:38815583]. In developing neurons it acts as an axonally distributed ribosome receptor that binds mRNAs encoding axonal membrane proteins and supports their local translation on axonal ER tubules, with RRBP1 disruption causing defects in axon morphology [PMID:38815583]. Beyond constitutive ER-ribosome coupling, RRBP1 is mobilized in stress responses: during mitochondrial protein import stress, cytosol-retained NLRX1 recruits RRBP1 to the mitochondrial vicinity, where the NLRX1/RRBP1 complex directs LC3 recruitment and lipidation to drive mitophagosome formation independently of canonical PINK1 signaling [PMID:35752171]. RRBP1 also supports cell survival under ER stress, where it enhances GRP78 protein levels and is implicated in stabilizing UPR-component mRNAs, and its overexpression rescues ER-stress-induced apoptosis [PMID:23318453]; its abundance is further controlled by the deubiquitinase USP35, which directly binds and deubiquitinates RRBP1 to prevent its proteasomal degradation [PMID:34618999]. These pro-survival activities underlie an oncogenic role, including regulation of the Hippo effector YAP1 to confer cisplatin resistance [PMID:33762722]. A recurrent RRBP1-ALK gene fusion produces a constitutively active, cytoplasmic/perinuclear ALK oncoprotein in epithelioid inflammatory myofibroblastic sarcoma [PMID:27874193].","teleology":[{"year":2012,"claim":"Establishing where RRBP1 resides and that it is broadly upregulated in tumors set the stage for a survival-associated function, but provided no mechanism.","evidence":"Immunohistochemistry of breast carcinoma tissue microarrays with public expression data integration","pmids":["22709790"],"confidence":"Low","gaps":["IHC localization only with no functional experiment","no mechanistic link between overexpression and tumor phenotype","does not address why RRBP1 is elevated"]},{"year":2013,"claim":"Loss- and gain-of-function in lung cancer cells showed RRBP1 protects cells from ER stress, answering whether its overexpression is functionally consequential by linking it to GRP78 and UPR-component mRNA stability.","evidence":"shRNA knockdown and ectopic overexpression with ER stress agents and viability/IHC assays in lung cancer cells","pmids":["23318453"],"confidence":"Medium","gaps":["no direct biochemical reconstitution of how RRBP1 enhances GRP78","mechanism of mRNA stabilization unresolved","single lab"]},{"year":2016,"claim":"Identification of a recurrent RRBP1-ALK fusion answered whether RRBP1 contributes to oncogenesis structurally, showing the RRBP1 portion drives a constitutively active, distinctively localized ALK kinase.","evidence":"ALK immunoprecipitation plus mass spectrometry, FISH and IHC across three EIMS tumor cases","pmids":["27874193"],"confidence":"High","gaps":["which RRBP1 domains mediate constitutive ALK activation not dissected","downstream signaling of the fusion not characterized"]},{"year":2016,"claim":"Mapping an IRES in the RRBP1 5' UTR addressed how RRBP1 is translated under stress, showing La-autoantigen-dependent cap-independent initiation that could sustain RRBP1 production when cap-dependent translation is suppressed.","evidence":"IRES reporter assays, RNA pulldown, deletion mapping, and La overexpression/knockdown under drug treatment or serum starvation in hepatocellular carcinoma cells","pmids":["27447629"],"confidence":"Medium","gaps":["physiological contribution of IRES to RRBP1 protein levels in vivo unquantified","link between IRES-driven translation and the survival phenotype not established"]},{"year":2021,"claim":"Discovery that USP35 deubiquitinates and stabilizes RRBP1 answered how RRBP1 abundance is post-translationally controlled and connected this to ER-stress survival.","evidence":"iTRAQ proteomics, Co-IP, ubiquitination and proteasome-inhibitor assays, KD/OE and apoptosis assays in NSCLC cells","pmids":["34618999"],"confidence":"Medium","gaps":["E3 ligase opposing USP35 not identified","ubiquitination site on RRBP1 not mapped","single lab"]},{"year":2021,"claim":"Linking RRBP1 to YAP1 regulation answered how RRBP1 drives chemoresistance, defining a Hippo-effector axis whose disruption restores drug sensitivity.","evidence":"RNA-seq, proteomics, RRBP1 knockout and pharmacological inhibition (Radezolid), YAP1 analysis and PDC xenografts in OSCC","pmids":["33762722"],"confidence":"Medium","gaps":["molecular mechanism connecting RRBP1 to YAP1 regulation unresolved","whether the link is direct or via translation/ER stress unknown"]},{"year":2022,"claim":"Identifying the NLRX1/RRBP1 complex answered how an ER ribosome receptor participates in mitochondrial quality control, defining a PINK1-independent mitophagy route triggered by mitochondrial import stress.","evidence":"Reciprocal Co-IP, RRBP1 relocalization imaging, NLRX1 KO and RRBP1 depletion, LC3 lipidation and in vivo skeletal muscle mitophagy assays","pmids":["35752171"],"confidence":"High","gaps":["how RRBP1 nucleates LC3 lipidation mechanistically unclear","structural basis of NLRX1-RRBP1 interaction unknown"]},{"year":2024,"claim":"Demonstrating RRBP1 as an axonal ribosome receptor that binds membrane-protein mRNAs established its core physiological function in spatially organizing local translation for axon development.","evidence":"Nanoscale-resolution imaging, ribosome contact mapping, mRNA binding assays, and RRBP1 loss-of-function with axon morphology readouts in rat hippocampal neurons","pmids":["38815583"],"confidence":"High","gaps":["selectivity determinants for which mRNAs RRBP1 binds unresolved","whether axonal and stress/cancer functions share the same molecular activity not addressed"]},{"year":null,"claim":"How RRBP1's ribosome-receptor activity is mechanistically reused across local translation, ER-stress survival, mitophagy, and oncogenic YAP1 signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unifying biochemical mechanism connecting ribosome anchoring to UPR/GRP78 and YAP1 outputs","no structural model of RRBP1 domains driving each function","direct RNA-binding determinants not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,4,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6]}],"complexes":["NLRX1/RRBP1 complex"],"partners":["NLRX1","USP35","ALK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2E9","full_name":"Ribosome-binding protein 1","aliases":["180 kDa ribosome receptor homolog","RRp","ES/130-related protein","Ribosome receptor protein"],"length_aa":1410,"mass_kda":152.5,"function":"Acts as a ribosome receptor and mediates interaction between the ribosome and the endoplasmic reticulum membrane","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9P2E9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RRBP1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"EEF1G","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RRBP1","total_profiled":1310},"omim":[{"mim_id":"601418","title":"RIBOSOME BINDING PROTEIN 1; RRBP1","url":"https://www.omim.org/entry/601418"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"pancreas","ntpm":469.5}],"url":"https://www.proteinatlas.org/search/RRBP1"},"hgnc":{"alias_symbol":["ES/130","hES","p180"],"prev_symbol":[]},"alphafold":{"accession":"Q9P2E9","domains":[{"cath_id":"-","chopping":"720-979","consensus_level":"medium","plddt":89.4633,"start":720,"end":979}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2E9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2E9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2E9-F1-predicted_aligned_error_v6.png","plddt_mean":69.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRBP1","jax_strain_url":"https://www.jax.org/strain/search?query=RRBP1"},"sequence":{"accession":"Q9P2E9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2E9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2E9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2E9"}},"corpus_meta":[{"pmid":"12548545","id":"PMC_12548545","title":"HES 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embryos.","date":"2004","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15081366","citation_count":20,"is_preprint":false},{"pmid":"36525794","id":"PMC_36525794","title":"Liraglutide ameliorates gentamicin-induced acute kidney injury in rats via PGC-1α- mediated mitochondrial biogenesis: Involvement of PKA/CREB and Notch/Hes-1 signaling pathways.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36525794","citation_count":19,"is_preprint":false},{"pmid":"12065598","id":"PMC_12065598","title":"The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12065598","citation_count":18,"is_preprint":false},{"pmid":"18215326","id":"PMC_18215326","title":"Human embryonic stem cell (hES) derived dendritic cells are functionally normal and are susceptible to HIV-1 infection.","date":"2008","source":"AIDS research and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/18215326","citation_count":18,"is_preprint":false},{"pmid":"34715307","id":"PMC_34715307","title":"Multiple functions of Hes genes in the proliferation and differentiation of neural stem cells.","date":"2021","source":"Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft","url":"https://pubmed.ncbi.nlm.nih.gov/34715307","citation_count":17,"is_preprint":false},{"pmid":"20131884","id":"PMC_20131884","title":"Spatially resolved quantification of E-cadherin on target hES cells.","date":"2010","source":"The journal of physical chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/20131884","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51276,"output_tokens":2725,"usd":0.097351,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9483,"output_tokens":3081,"usd":0.06222,"stage2_stop_reason":"end_turn"},"total_usd":0.159571,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical RRBP1 protein (ribosome-binding protein 1, also known as ES/130 or p180). The aliases \"ES/130\" and \"hES\" in the HGNC field refer to RRBP1, NOT to human embryonic stem cells. I need to carefully distinguish RRBP1-specific papers from the many papers about HES/Notch signaling (a completely different gene family), hydroxyethyl starch (HES), or human embryonic stem (hES) cells.\n\nPapers directly about RRBP1:\n- [19]: RRBP1-ALK fusion in cancer\n- [24]: RRBP1 in lung cancer, GRP78, ER stress\n- [33]: RRBP1 in mitophagy with NLRX1\n- [60]: USP35 stabilizes RRBP1\n- [62]: P180/RRBP1 in axonal ER translation\n- [72]: RRBP1 overexpression in breast cancer\n- [81]: CircVPS13C interacts with RRBP1 (circRNA paper - exclude as non-protein product)\n- [85]: RRBP1 and Hippo/YAP1 in cisplatin resistance\n- [94]: La autoantigen and RRBP1 IRES-mediated translation\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"RRBP1 knockdown by shRNA in lung cancer cells caused ER stress, reduced cell viability and tumorigenicity, and significantly decreased GRP78 protein expression. Ectopic overexpression of RRBP1 alleviated apoptosis induced by ER stress agents (tunicamycin, 2-deoxy-D-glucose, doxorubicin) by enhancing GRP78 protein expression, and RRBP1 was implicated in regulating mRNA stability of UPR components including ATF6 and GRP78.\",\n      \"method\": \"shRNA knockdown, ectopic overexpression, cell viability assays, immunohistochemistry, bioinformatic correlation (GSE10072)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype plus gain-of-function rescue, single lab, two orthogonal approaches (KD + OE), but no direct biochemical reconstitution of RRBP1-GRP78 mechanism\",\n      \"pmids\": [\"23318453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A novel recurrent RRBP1-ALK gene fusion was identified in epithelioid inflammatory myofibroblastic sarcoma. The RRBP1-ALK fusion produced constitutively activated ALK oncoprotein with cytoplasmic/perinuclear ALK localization (distinct from nuclear membranous localization seen with RANBP2-ALK fusions), identified by ALK immunoprecipitation followed by mass spectrometry.\",\n      \"method\": \"ALK immunoprecipitation, mass spectrometry, FISH, immunohistochemistry\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — protein purification plus mass spectrometry identification, replicated in multiple independent tumor cases (3 EIMS cases with RRBP1-ALK confirmed), multiple orthogonal methods\",\n      \"pmids\": [\"27874193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During mitochondrial protein import stress (MPIS), cytosol-retained NLRX1 recruits RRBP1 (a ribosome-binding transmembrane protein of the ER) which relocates to the mitochondrial vicinity. The NLRX1/RRBP1 complex controls LC3 recruitment and lipidation at the site of mitophagosome formation, independently of canonical PINK1 signaling. RRBP1 interaction with NLRX1 was demonstrated and RRBP1 relocation to mitochondrial vicinity during MPIS was documented.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/live imaging of RRBP1 relocalization, genetic loss-of-function (NLRX1 KO, RRBP1 depletion), LC3 lipidation assays, in vivo skeletal muscle mitophagy assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing NLRX1/RRBP1 complex, direct localization experiment with functional consequence, multiple genetic models (KO, depletion), in vivo validation, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"35752171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP35 (a deubiquitinating enzyme) directly interacts with RRBP1 and prevents its proteasomal degradation by deubiquitination, thereby stabilizing RRBP1. Functionally, USP35 alleviates ER stress-induced apoptosis in non-small cell lung cancer cells through this stabilization of RRBP1.\",\n      \"method\": \"iTRAQ comparative proteomics, Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, genetic KD/OE, cell apoptosis assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction verified by Co-IP, proteasomal degradation demonstrated, functional rescue experiment, single lab\",\n      \"pmids\": [\"34618999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"P180/RRBP1 functions as an axonally distributed ribosome receptor in developing rat hippocampal neurons. RRBP1 regulates local mRNA translation on axonal ER tubules and binds to mRNAs enriched for axonal membrane proteins. Impairment of axonal ER-ribosome interactions via RRBP1 disruption causes defects in axon morphology, demonstrating that RRBP1-mediated ER-ribosome contacts are required for proper axon development.\",\n      \"method\": \"Nanoscale resolution imaging, ribosome contact mapping, RRBP1 loss-of-function, mRNA binding assays, axon morphology readouts, live neuron imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with functional consequence, mRNA binding demonstrated, loss-of-function with defined morphological phenotype, nanoscale imaging providing structural resolution, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"38815583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RRBP1 protein is overexpressed in 84% of breast carcinoma cases. Subcellular localization of RRBP1 was predominantly cytoplasmic with intense perinuclear staining, consistent with its ER membrane localization.\",\n      \"method\": \"Immunohistochemical labeling of tissue microarrays (219 breast carcinoma cases), integration with public gene expression databases\",\n      \"journal\": \"Clinical proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — IHC-based subcellular localization with no functional follow-up, single method, no mechanistic experiment\",\n      \"pmids\": [\"22709790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRBP1 regulates YAP1 (Yes-associated protein 1), a key effector of the Hippo pathway, to induce cisplatin resistance in oral squamous cell carcinoma. Genetic knockout or pharmacological inhibition (Radezolid) of RRBP1 restored cisplatin-mediated cell death in chemoresistant OSCC cells and reduced tumor burden in PDC xenografts.\",\n      \"method\": \"RNA sequencing, global proteomic profiling, RRBP1 knockout, pharmacological inhibition, PDC xenograft experiments, YAP1 expression analysis\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular target (YAP1) and functional phenotype, in vivo xenograft validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"33762722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The 5' UTR of RRBP1 mRNA contains an internal ribosome entry site (IRES). La autoantigen binds to the RRBP1 IRES element and facilitates cap-independent translation initiation under cellular stress conditions (chemotherapeutic drug treatment or serum starvation). Two apical GARR loops within the IRES are important for La binding. The core IRES activity was mapped to nucleotides -237 to -58.\",\n      \"method\": \"IRES reporter assays, RNA pulldown/binding assays, deletion mapping, La overexpression and knockdown, stress induction experiments in hepatocellular carcinoma cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein binding assay plus functional IRES reporter with deletion mapping, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"27447629\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRBP1 (ribosome-binding protein 1/P180) is an ER transmembrane ribosome receptor that anchors ribosomes to the rough ER membrane; it regulates local mRNA translation at axonal ER tubules (binding mRNAs for membrane proteins), forms a complex with NLRX1 to control LC3 lipidation and mitophagosome formation in response to mitochondrial protein import stress, is stabilized by the deubiquitinase USP35 to protect against ER stress-induced apoptosis, promotes cancer cell survival by enhancing GRP78 expression and by regulating the Hippo effector YAP1 to drive chemoresistance, and can be translocated as a fusion oncoprotein (RRBP1-ALK) driving constitutive ALK kinase activity in epithelioid inflammatory myofibroblastic sarcoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRBP1 (P180) is an endoplasmic reticulum transmembrane ribosome receptor that anchors ribosomes to the ER membrane and organizes local, compartmentalized translation [#4]. In developing neurons it acts as an axonally distributed ribosome receptor that binds mRNAs encoding axonal membrane proteins and supports their local translation on axonal ER tubules, with RRBP1 disruption causing defects in axon morphology [#4]. Beyond constitutive ER-ribosome coupling, RRBP1 is mobilized in stress responses: during mitochondrial protein import stress, cytosol-retained NLRX1 recruits RRBP1 to the mitochondrial vicinity, where the NLRX1/RRBP1 complex directs LC3 recruitment and lipidation to drive mitophagosome formation independently of canonical PINK1 signaling [#2]. RRBP1 also supports cell survival under ER stress, where it enhances GRP78 protein levels and is implicated in stabilizing UPR-component mRNAs, and its overexpression rescues ER-stress-induced apoptosis [#0]; its abundance is further controlled by the deubiquitinase USP35, which directly binds and deubiquitinates RRBP1 to prevent its proteasomal degradation [#3]. These pro-survival activities underlie an oncogenic role, including regulation of the Hippo effector YAP1 to confer cisplatin resistance [#6]. A recurrent RRBP1-ALK gene fusion produces a constitutively active, cytoplasmic/perinuclear ALK oncoprotein in epithelioid inflammatory myofibroblastic sarcoma [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing where RRBP1 resides and that it is broadly upregulated in tumors set the stage for a survival-associated function, but provided no mechanism.\",\n      \"evidence\": \"Immunohistochemistry of breast carcinoma tissue microarrays with public expression data integration\",\n      \"pmids\": [\"22709790\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"IHC localization only with no functional experiment\", \"no mechanistic link between overexpression and tumor phenotype\", \"does not address why RRBP1 is elevated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss- and gain-of-function in lung cancer cells showed RRBP1 protects cells from ER stress, answering whether its overexpression is functionally consequential by linking it to GRP78 and UPR-component mRNA stability.\",\n      \"evidence\": \"shRNA knockdown and ectopic overexpression with ER stress agents and viability/IHC assays in lung cancer cells\",\n      \"pmids\": [\"23318453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no direct biochemical reconstitution of how RRBP1 enhances GRP78\", \"mechanism of mRNA stabilization unresolved\", \"single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of a recurrent RRBP1-ALK fusion answered whether RRBP1 contributes to oncogenesis structurally, showing the RRBP1 portion drives a constitutively active, distinctively localized ALK kinase.\",\n      \"evidence\": \"ALK immunoprecipitation plus mass spectrometry, FISH and IHC across three EIMS tumor cases\",\n      \"pmids\": [\"27874193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"which RRBP1 domains mediate constitutive ALK activation not dissected\", \"downstream signaling of the fusion not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapping an IRES in the RRBP1 5' UTR addressed how RRBP1 is translated under stress, showing La-autoantigen-dependent cap-independent initiation that could sustain RRBP1 production when cap-dependent translation is suppressed.\",\n      \"evidence\": \"IRES reporter assays, RNA pulldown, deletion mapping, and La overexpression/knockdown under drug treatment or serum starvation in hepatocellular carcinoma cells\",\n      \"pmids\": [\"27447629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"physiological contribution of IRES to RRBP1 protein levels in vivo unquantified\", \"link between IRES-driven translation and the survival phenotype not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that USP35 deubiquitinates and stabilizes RRBP1 answered how RRBP1 abundance is post-translationally controlled and connected this to ER-stress survival.\",\n      \"evidence\": \"iTRAQ proteomics, Co-IP, ubiquitination and proteasome-inhibitor assays, KD/OE and apoptosis assays in NSCLC cells\",\n      \"pmids\": [\"34618999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP35 not identified\", \"ubiquitination site on RRBP1 not mapped\", \"single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking RRBP1 to YAP1 regulation answered how RRBP1 drives chemoresistance, defining a Hippo-effector axis whose disruption restores drug sensitivity.\",\n      \"evidence\": \"RNA-seq, proteomics, RRBP1 knockout and pharmacological inhibition (Radezolid), YAP1 analysis and PDC xenografts in OSCC\",\n      \"pmids\": [\"33762722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular mechanism connecting RRBP1 to YAP1 regulation unresolved\", \"whether the link is direct or via translation/ER stress unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying the NLRX1/RRBP1 complex answered how an ER ribosome receptor participates in mitochondrial quality control, defining a PINK1-independent mitophagy route triggered by mitochondrial import stress.\",\n      \"evidence\": \"Reciprocal Co-IP, RRBP1 relocalization imaging, NLRX1 KO and RRBP1 depletion, LC3 lipidation and in vivo skeletal muscle mitophagy assays\",\n      \"pmids\": [\"35752171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how RRBP1 nucleates LC3 lipidation mechanistically unclear\", \"structural basis of NLRX1-RRBP1 interaction unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating RRBP1 as an axonal ribosome receptor that binds membrane-protein mRNAs established its core physiological function in spatially organizing local translation for axon development.\",\n      \"evidence\": \"Nanoscale-resolution imaging, ribosome contact mapping, mRNA binding assays, and RRBP1 loss-of-function with axon morphology readouts in rat hippocampal neurons\",\n      \"pmids\": [\"38815583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"selectivity determinants for which mRNAs RRBP1 binds unresolved\", \"whether axonal and stress/cancer functions share the same molecular activity not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RRBP1's ribosome-receptor activity is mechanistically reused across local translation, ER-stress survival, mitophagy, and oncogenic YAP1 signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unifying biochemical mechanism connecting ribosome anchoring to UPR/GRP78 and YAP1 outputs\", \"no structural model of RRBP1 domains driving each function\", \"direct RNA-binding determinants not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\"NLRX1/RRBP1 complex\"],\n    \"partners\": [\"NLRX1\", \"USP35\", \"ALK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}