{"gene":"RNF167","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2012,"finding":"RNF167 is a transmembrane RING domain-containing E3 ubiquitin ligase predominantly localized to lysosomes (with a subpopulation on the neuronal surface) that ubiquitinates AMPA receptors (AMPARs) in an activity-dependent manner, reducing their surface expression and regulating AMPAR-mediated synaptic currents without affecting NMDAR currents.","method":"Screen for transmembrane RING E3s; RING-dead mutant and shRNA knockdown in hippocampal neurons; surface expression assays; electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (loss-of-function via RING mutant and shRNA, surface expression assay, electrophysiology), replicated across conditions in a focused study","pmids":["23129617"],"is_preprint":false},{"year":2014,"finding":"Point mutations in the RING domain of RNF167 abrogate its ubiquitin ligase activity; additionally, the PA (protease-associated) domain is required for endosomal localization of RNF167, and PA domain mutations identified in human tumors render RNF167 ligase-active but mislocalized, impairing substrate targeting.","method":"Tumor mutation analysis; functional ubiquitin ligase assays with RING mutants; subcellular localization experiments with PA domain mutants","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ligase assays plus localization experiments in a single lab; two orthogonal methods","pmids":["24387786"],"is_preprint":false},{"year":2016,"finding":"RNF167 ubiquitinates Arl8B at lysine K141, leading to its degradation; this regulation controls Arl8B-dependent lysosome positioning and endocytic trafficking to lysosomes, as demonstrated by the ubiquitination-defective Arl8B K141R mutant counteracting RNF167 function.","method":"Proximity-dependent biotin labeling (BioID) for substrate identification; in vitro ubiquitination assay; overexpression and knockdown studies; K141R mutant rescue experiments","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — substrate identified by BioID, confirmed by in vitro ubiquitination, site-specific mutagenesis (K141R), and functional readouts (lysosome positioning/endocytic trafficking), single lab but multiple orthogonal methods","pmids":["27808481"],"is_preprint":false},{"year":2021,"finding":"RNF167 promotes K29-linked polyubiquitination and proteasomal degradation of CASTOR1 (cytosolic arginine sensor for mTORC1 subunit 1); AKT phosphorylates CASTOR1 at S14, increasing its binding to RNF167 and thus its ubiquitination and degradation, which activates mTORC1 independently of arginine and promotes breast cancer progression.","method":"Co-immunoprecipitation; ubiquitination assays with linkage-specific analysis; phosphorylation site mutagenesis (S14); AKT kinase assay; xenograft tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination assays, specific K29-linkage determination, phospho-site mutagenesis, binding assays, and in vivo tumor models in a single focused study","pmids":["33594058"],"is_preprint":false},{"year":2021,"finding":"RNF167 functionally interacts with E2 ubiquitin-conjugating enzymes UBE2D1 and UBE2N in endosomes and lysosomes; in vitro, polyubiquitination of GluA2 (AMPAR subunit) requires priming by an initiating E2 interacting with RNF167 followed by UBE2N-mediated chain elongation; pharmacological inhibition of UBE2N in hippocampal neurons reduces AMPA-induced GluA2 ubiquitination.","method":"In vitro autoubiquitination and binding assays; kinetic analysis (dissociation constants); fluorescence microscopy co-localization; in vitro polyubiquitination assay with GluA2; pharmacological UBE2N inhibition in neurons","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitination with defined E2s, kinetic measurements, mutagenesis-informed modeling, and neuronal pharmacological validation in single lab with multiple orthogonal methods","pmids":["33650289"],"is_preprint":false},{"year":2022,"finding":"RNF167 and the deubiquitinase STAMBPL1 act in concert to control polyubiquitination of Sestrin2 in response to leucine availability; RNF167-mediated ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling.","method":"Identification of RNF167 as Sestrin2 E3 ligase; co-immunoprecipitation of ubiquitinated Sestrin2 with GATOR2; knockout/correction of STAMBPL1; cell-permeable peptide blocking STAMBPL1-Sestrin2 interaction; xenograft tumor assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic KO, epistasis through nutrient signaling, and in vivo xenograft validation in a single rigorous study","pmids":["35114100"],"is_preprint":false},{"year":2022,"finding":"RNF167 ubiquitinates Rab7 GTPase; Rab7 must be in its GTP-bound (active), membrane-anchored form to be accessible for RNF167-mediated ubiquitination; RNF167 activity maintains Rab7 membrane localization and affects endosomal vesicle size; Rab7 ubiquitination by RNF167 is impaired by Charcot-Marie-Tooth Type 2B disease variants.","method":"Co-immunoprecipitation; in vitro ubiquitination assays; subcellular fractionation; epifluorescence microscopy; RNF167 knockdown; CMT2B variant analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ubiquitination confirmed, GTP-dependence characterized, fractionation, and disease-variant functional analysis in a single lab","pmids":["35887194"],"is_preprint":false},{"year":2023,"finding":"RNF167 interacts with Tollip via Tollip's C-terminal CUE domain and attaches K33-linked polyubiquitin chains to Tollip at lysine K235; this ubiquitination is required for Tollip to inhibit TNF-α-induced NF-κB and MAPK (JNK) activation, as the Tollip K235R substitution abolishes suppression of these cascades.","method":"Co-immunoprecipitation; ubiquitination assays with linkage-type determination; site-directed mutagenesis (K235R); TNF-α stimulation with NF-κB/MAPK readouts","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, K33 linkage determination, functional mutagenesis with defined signaling readouts; single lab","pmids":["37410058"],"is_preprint":false},{"year":2025,"finding":"RNF167 promotes K6-linked polyubiquitination of RIG-I/MDA5 within their CARD domains and K11-linked polyubiquitination within their CTD domains; K6-ubiquitinated RLRs are recognized by the autophagy cargo adaptor p62 and degraded via selective autophagy, while K11-ubiquitinated RLRs are degraded by the proteasome; through this dual mechanism RNF167 negatively regulates RLR-triggered type I interferon signaling.","method":"Ubiquitin linkage-specific assays; domain mapping of ubiquitination sites; p62 interaction studies; autophagy and proteasome inhibition experiments; IFN-I signaling readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — linkage-specific ubiquitination assays, domain-level site mapping, identification of p62 as reader, dual pathway degradation dissection with pathway inhibitors, single lab but multiple orthogonal methods","pmids":["39994288"],"is_preprint":false},{"year":2025,"finding":"RNF167 forms a heterodimer with RNF13; this RNF13-RNF167 heterodimer interacts with iduronate 2-sulfatase (IDS) and alters IDS glycosylation and maturation differently than either ligase alone; heterodimer formation modifies the lysosomal trafficking of both RNF13 and RNF167.","method":"Co-immunoprecipitation; AlphaFold3-guided interaction prediction; glycosylation and maturation assays; subcellular localization analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, Co-IP-based heterodimer identification without full mechanistic reconstitution of the complex","pmids":["bio_10.1101_2025.06.20.660705"],"is_preprint":true},{"year":2025,"finding":"SMAD3 interacts with RNF167 and STAMBPL1 (by co-immunoprecipitation) and stabilizes Sestrin2 protein levels by modulating the balance of RNF167-mediated ubiquitination and STAMBPL1-mediated deubiquitination, thereby regulating mTORC1 activity and gastric cancer cell behaviors.","method":"Co-immunoprecipitation; Western blotting; immunofluorescence; SMAD3 overexpression and knockdown in GC cells","journal":"Cell division","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP only for interaction, no direct ubiquitination reconstitution for SMAD3-RNF167 axis","pmids":["40751214"],"is_preprint":false}],"current_model":"RNF167 is a transmembrane RING-type E3 ubiquitin ligase resident in endosomes and lysosomes (localization requiring an intact PA domain) that ubiquitinates multiple substrates—including AMPA receptor subunits (via UBE2D1/UBE2N E2s), Arl8B (K141, controlling lysosome positioning), CASTOR1 (K29-linked, activated by AKT-mediated S14 phosphorylation to activate mTORC1), Sestrin2 (promoting GATOR2 interaction to inhibit mTORC1, counteracted by deubiquitinase STAMBPL1), Tollip (K33-linked at K235, enabling suppression of TNF-α/NF-κB/MAPK signaling), RIG-I/MDA5 (K6-linked CARD degradation via selective autophagy/p62 and K11-linked CTD degradation via proteasome to dampen interferon signaling), and Rab7 (requiring GTP-bound membrane-anchored Rab7); it also forms a heterodimer with the related ligase RNF13 that alters lysosomal trafficking of both proteins."},"narrative":{"mechanistic_narrative":"RNF167 is a transmembrane RING-type E3 ubiquitin ligase resident in endosomes and lysosomes that controls membrane-receptor abundance, organelle dynamics, nutrient signaling, and innate immunity through substrate-specific ubiquitination [PMID:23129617, PMID:27808481, PMID:33594058]. Its catalytic activity requires an intact RING domain, while its protease-associated (PA) domain governs endosomal/lysosomal localization; tumor-derived PA mutations leave the enzyme catalytically active but mislocalized and unable to reach substrates [PMID:24387786]. RNF167 builds ubiquitin chains by partnering with E2 enzymes UBE2D1 and UBE2N, where an initiating E2 primes the substrate and UBE2N elongates the chain, as reconstituted for the AMPA receptor subunit GluA2 to drive activity-dependent reduction of surface AMPA receptors and synaptic currents [PMID:23129617, PMID:33650289]. The ligase shapes the endolysosomal system by ubiquitinating Arl8B at K141 to control lysosome positioning and by ubiquitinating GTP-bound, membrane-anchored Rab7 to maintain its membrane localization and regulate endosomal vesicle size [PMID:27808481, PMID:35887194]. RNF167 is a node in mTORC1 control, acting bidirectionally: it drives K29-linked degradation of the arginine sensor CASTOR1 (enhanced by AKT-mediated CASTOR1 S14 phosphorylation) to activate mTORC1, and it ubiquitinates Sestrin2 to promote its GATOR2 interaction and inhibit mTORC1, an event reversed by the deubiquitinase STAMBPL1 [PMID:33594058, PMID:35114100]. In immune and inflammatory signaling it attaches K33-linked chains to Tollip at K235 to enable suppression of TNF-α-induced NF-κB and MAPK activation, and it dampens type I interferon responses by directing RIG-I/MDA5 to dual degradation routes—K6-linked CARD ubiquitination read by p62 for selective autophagy and K11-linked CTD ubiquitination for proteasomal turnover [PMID:37410058, PMID:39994288].","teleology":[{"year":2012,"claim":"Established RNF167 as a transmembrane RING E3 ligase that acts at the neuronal surface to control synaptic strength, defining its first physiological substrate.","evidence":"Transmembrane RING E3 screen with RING-dead mutant and shRNA in hippocampal neurons, surface AMPAR assays, electrophysiology","pmids":["23129617"],"confidence":"High","gaps":["Ubiquitination site on AMPAR subunits not mapped","E2 partners and chain linkage not yet defined"]},{"year":2014,"claim":"Separated the catalytic and targeting modules of RNF167, showing the RING domain is required for ligase activity while the PA domain dictates endosomal localization, and linking PA mutations to cancer-associated mislocalization.","evidence":"Tumor mutation analysis with RING and PA domain mutants, in vitro ligase assays, subcellular localization","pmids":["24387786"],"confidence":"Medium","gaps":["How the PA domain achieves membrane targeting at the molecular level unresolved","Functional consequence of mislocalization on specific substrates not tested"]},{"year":2016,"claim":"Extended RNF167 function to organelle dynamics by identifying Arl8B as a substrate whose K141 ubiquitination controls lysosome positioning and endocytic trafficking.","evidence":"BioID substrate screen, in vitro ubiquitination, K141R rescue, lysosome positioning readouts","pmids":["27808481"],"confidence":"High","gaps":["Chain linkage type on Arl8B not specified","Upstream signals regulating this event unknown"]},{"year":2021,"claim":"Defined the enzymatic logic of RNF167 chain assembly, showing an initiating E2 primes the substrate and UBE2N elongates the chain, validated for GluA2 and confirmed in neurons.","evidence":"In vitro reconstitution with defined E2s, kinetic binding measurements, GluA2 polyubiquitination assay, UBE2N inhibition in neurons","pmids":["33650289"],"confidence":"High","gaps":["Identity of the priming E2 not fully resolved","Whether the same E2 logic applies to all substrates untested"]},{"year":2021,"claim":"Connected RNF167 to mTORC1 activation by showing AKT-phosphorylated CASTOR1 is degraded via K29-linked ubiquitination, providing an arginine-independent route to mTORC1 activity in cancer.","evidence":"Co-IP, K29 linkage-specific ubiquitination assays, S14 phospho-mutagenesis, AKT kinase assay, xenograft models","pmids":["33594058"],"confidence":"High","gaps":["Whether CASTOR1 turnover occurs at the lysosomal membrane unclear","Counteracting deubiquitinase not identified"]},{"year":2022,"claim":"Revealed RNF167 as a bidirectional mTORC1 regulator, ubiquitinating Sestrin2 to promote GATOR2 binding and inhibit mTORC1, opposed by the deubiquitinase STAMBPL1 under leucine control.","evidence":"E3 identification, Co-IP of ubiquitinated Sestrin2 with GATOR2, STAMBPL1 KO/correction, blocking peptide, xenografts","pmids":["35114100"],"confidence":"High","gaps":["How leucine availability is sensed upstream of this axis unclear","Reconciliation of opposing CASTOR1/Sestrin2 effects on mTORC1 not addressed"]},{"year":2022,"claim":"Showed RNF167 ubiquitinates GTP-bound, membrane-anchored Rab7 to sustain Rab7 membrane localization and regulate endosomal vesicle size, with disease variants impairing the reaction.","evidence":"Co-IP, in vitro ubiquitination, subcellular fractionation, microscopy, CMT2B variant analysis","pmids":["35887194"],"confidence":"Medium","gaps":["Ubiquitination site and chain linkage on Rab7 not defined","Mechanistic link to Charcot-Marie-Tooth pathology not established"]},{"year":2023,"claim":"Placed RNF167 in inflammatory signaling control by showing K33-linked ubiquitination of Tollip at K235 is required for suppression of TNF-α-induced NF-κB and MAPK activation.","evidence":"Reciprocal Co-IP via Tollip CUE domain, K33 linkage determination, K235R mutagenesis, TNF-α-stimulated signaling readouts","pmids":["37410058"],"confidence":"Medium","gaps":["Downstream effector engaged by K33-ubiquitinated Tollip unclear","Physiological setting in vivo not tested"]},{"year":2025,"claim":"Defined a dual-pathway mechanism by which RNF167 dampens antiviral interferon signaling, routing RIG-I/MDA5 to autophagy via K6/p62 and to the proteasome via K11.","evidence":"Linkage-specific ubiquitination assays, domain-level site mapping, p62 interaction studies, autophagy/proteasome inhibition, IFN-I readouts","pmids":["39994288"],"confidence":"High","gaps":["Trigger determining K6 versus K11 chain choice unknown","Whether localization at endolysosomes is required for RLR targeting untested"]},{"year":2025,"claim":"Proposed that RNF167 heterodimerizes with RNF13 to co-regulate IDS maturation and the lysosomal trafficking of both ligases, extending RNF167 function into partner-modulated activity.","evidence":"Co-IP, AlphaFold3-guided prediction, glycosylation/maturation assays, localization analysis (preprint)","pmids":["bio_10.1101_2025.06.20.660705"],"confidence":"Low","gaps":["Heterodimer identified by Co-IP without reconstitution of the complex","Catalytic consequence of heterodimerization not directly demonstrated","Whether IDS is a direct substrate unresolved"]},{"year":2025,"claim":"Implicated SMAD3 as an upstream regulator that stabilizes Sestrin2 by tuning the RNF167/STAMBPL1 ubiquitination balance in gastric cancer.","evidence":"Co-IP, Western blot, immunofluorescence, SMAD3 gain/loss-of-function in gastric cancer cells","pmids":["40751214"],"confidence":"Low","gaps":["Interaction shown by Co-IP only without ubiquitination reconstitution for the SMAD3 axis","Whether SMAD3 acts on RNF167 catalysis or substrate access unclear"]},{"year":null,"claim":"How RNF167 selects among its diverse substrates and assembles distinct chain linkages (K6, K11, K29, K33) in different subcellular and signaling contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or E2 engagement","Determinants of linkage-type specificity unknown","Spatial coupling between localization and substrate choice undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,4,5,6,7,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,6,7,8]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,2,4,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,4,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,7,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,5,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4]}],"complexes":["RNF13-RNF167 heterodimer"],"partners":["UBE2D1","UBE2N","CASTOR1","SESN2","STAMBPL1","TOLLIP","RNF13","RAB7A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6Y7","full_name":"E3 ubiquitin-protein ligase RNF167","aliases":["RING finger protein 167"],"length_aa":350,"mass_kda":38.3,"function":"E3 ubiquitin-protein ligase that acts as a regulator of the TORC1 signaling pathway (PubMed:33594058, PubMed:35114100). Positively regulates the TORC1 signaling pathway independently of arginine levels: acts by catalyzing 'Lys-29'-polyubiquitination and degradation of CASTOR1, releasing the GATOR2 complex from CASTOR1 (PubMed:33594058). Also negatively regulates the TORC1 signaling pathway in response to leucine deprivation: acts by mediating 'Lys-63'-linked polyubiquitination of SESN2, promoting SESN2-interaction with the GATOR2 complex (PubMed:35114100). Also involved in protein trafficking and localization (PubMed:23129617, PubMed:23353890, PubMed:24387786, PubMed:27808481, PubMed:32409562). Acts as a regulator of synaptic transmission by mediating ubiquitination and degradation of AMPAR receptor GluA2/GRIA2 (PubMed:23129617, PubMed:33650289). Does not catalyze ubiquitination of GluA1/GRIA1 (PubMed:23129617). Also acts as a regulator of the recycling endosome pathway by mediating ubiquitination of VAMP3 (PubMed:23353890). Regulates lysosome positioning by catalyzing ubiquitination and degradation of ARL8B (PubMed:27808481). Plays a role in growth regulation involved in G1/S transition by mediating, possibly by mediating ubiquitination of SLC22A18 (PubMed:16314844). Acts with a limited set of E2 enzymes, such as UBE2D1 and UBE2N (PubMed:33650289)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q9H6Y7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF167","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"LAMP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RNF167","total_profiled":1310},"omim":[{"mim_id":"610431","title":"RING FINGER PROTEIN 167; RNF167","url":"https://www.omim.org/entry/610431"},{"mim_id":"602631","title":"SOLUTE CARRIER FAMILY 67, MEMBER 1; SLC67A1","url":"https://www.omim.org/entry/602631"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNF167"},"hgnc":{"alias_symbol":["DKFZP566H073"],"prev_symbol":[]},"alphafold":{"accession":"Q9H6Y7","domains":[{"cath_id":"3.50.30.30","chopping":"25-167","consensus_level":"high","plddt":93.762,"start":25,"end":167},{"cath_id":"3.30.40.10","chopping":"211-265","consensus_level":"high","plddt":89.0089,"start":211,"end":265}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6Y7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6Y7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6Y7-F1-predicted_aligned_error_v6.png","plddt_mean":78.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF167","jax_strain_url":"https://www.jax.org/strain/search?query=RNF167"},"sequence":{"accession":"Q9H6Y7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6Y7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6Y7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6Y7"}},"corpus_meta":[{"pmid":"35114100","id":"PMC_35114100","title":"E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression.","date":"2022","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/35114100","citation_count":73,"is_preprint":false},{"pmid":"23129617","id":"PMC_23129617","title":"Ubiquitin ligase RNF167 regulates AMPA receptor-mediated synaptic transmission.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23129617","citation_count":70,"is_preprint":false},{"pmid":"33594058","id":"PMC_33594058","title":"RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33594058","citation_count":41,"is_preprint":false},{"pmid":"24387786","id":"PMC_24387786","title":"Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13 identify the PA domain as a determinant for endosomal localization.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24387786","citation_count":30,"is_preprint":false},{"pmid":"27808481","id":"PMC_27808481","title":"RNF167 targets Arl8B for degradation to regulate lysosome positioning and endocytic trafficking.","date":"2016","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/27808481","citation_count":24,"is_preprint":false},{"pmid":"33650289","id":"PMC_33650289","title":"Functional interaction of ubiquitin ligase RNF167 with UBE2D1 and UBE2N promotes ubiquitination of AMPA receptor.","date":"2021","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/33650289","citation_count":13,"is_preprint":false},{"pmid":"37410058","id":"PMC_37410058","title":"RNF167-mediated ubiquitination of Tollip inhibits TNF-α-triggered NF-κB and MAPK activation.","date":"2023","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/37410058","citation_count":10,"is_preprint":false},{"pmid":"35887194","id":"PMC_35887194","title":"Membrane Targeting and GTPase Activity of Rab7 Are Required for Its Ubiquitination by RNF167.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35887194","citation_count":6,"is_preprint":false},{"pmid":"39994288","id":"PMC_39994288","title":"RNF167 mediates atypical ubiquitylation and degradation of RLRs via two distinct proteolytic pathways.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39994288","citation_count":4,"is_preprint":false},{"pmid":"40751214","id":"PMC_40751214","title":"SMAD3 orchestrates RNF167 and STAMBPL1-mediated Sestrin2 ubiquitination to drive gastric cancer progression.","date":"2025","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/40751214","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.20.660705","title":"RNF13 is a novel interactor of iduronate 2-sulfatase that modifies its glycosylation and maturation","date":"2025-06-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.20.660705","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7448,"output_tokens":3280,"usd":0.035772,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10637,"output_tokens":4189,"usd":0.078955,"stage2_stop_reason":"end_turn"},"total_usd":0.114727,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"RNF167 is a transmembrane RING domain-containing E3 ubiquitin ligase predominantly localized to lysosomes (with a subpopulation on the neuronal surface) that ubiquitinates AMPA receptors (AMPARs) in an activity-dependent manner, reducing their surface expression and regulating AMPAR-mediated synaptic currents without affecting NMDAR currents.\",\n      \"method\": \"Screen for transmembrane RING E3s; RING-dead mutant and shRNA knockdown in hippocampal neurons; surface expression assays; electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (loss-of-function via RING mutant and shRNA, surface expression assay, electrophysiology), replicated across conditions in a focused study\",\n      \"pmids\": [\"23129617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Point mutations in the RING domain of RNF167 abrogate its ubiquitin ligase activity; additionally, the PA (protease-associated) domain is required for endosomal localization of RNF167, and PA domain mutations identified in human tumors render RNF167 ligase-active but mislocalized, impairing substrate targeting.\",\n      \"method\": \"Tumor mutation analysis; functional ubiquitin ligase assays with RING mutants; subcellular localization experiments with PA domain mutants\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ligase assays plus localization experiments in a single lab; two orthogonal methods\",\n      \"pmids\": [\"24387786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNF167 ubiquitinates Arl8B at lysine K141, leading to its degradation; this regulation controls Arl8B-dependent lysosome positioning and endocytic trafficking to lysosomes, as demonstrated by the ubiquitination-defective Arl8B K141R mutant counteracting RNF167 function.\",\n      \"method\": \"Proximity-dependent biotin labeling (BioID) for substrate identification; in vitro ubiquitination assay; overexpression and knockdown studies; K141R mutant rescue experiments\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — substrate identified by BioID, confirmed by in vitro ubiquitination, site-specific mutagenesis (K141R), and functional readouts (lysosome positioning/endocytic trafficking), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27808481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF167 promotes K29-linked polyubiquitination and proteasomal degradation of CASTOR1 (cytosolic arginine sensor for mTORC1 subunit 1); AKT phosphorylates CASTOR1 at S14, increasing its binding to RNF167 and thus its ubiquitination and degradation, which activates mTORC1 independently of arginine and promotes breast cancer progression.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays with linkage-specific analysis; phosphorylation site mutagenesis (S14); AKT kinase assay; xenograft tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination assays, specific K29-linkage determination, phospho-site mutagenesis, binding assays, and in vivo tumor models in a single focused study\",\n      \"pmids\": [\"33594058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF167 functionally interacts with E2 ubiquitin-conjugating enzymes UBE2D1 and UBE2N in endosomes and lysosomes; in vitro, polyubiquitination of GluA2 (AMPAR subunit) requires priming by an initiating E2 interacting with RNF167 followed by UBE2N-mediated chain elongation; pharmacological inhibition of UBE2N in hippocampal neurons reduces AMPA-induced GluA2 ubiquitination.\",\n      \"method\": \"In vitro autoubiquitination and binding assays; kinetic analysis (dissociation constants); fluorescence microscopy co-localization; in vitro polyubiquitination assay with GluA2; pharmacological UBE2N inhibition in neurons\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitination with defined E2s, kinetic measurements, mutagenesis-informed modeling, and neuronal pharmacological validation in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33650289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF167 and the deubiquitinase STAMBPL1 act in concert to control polyubiquitination of Sestrin2 in response to leucine availability; RNF167-mediated ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling.\",\n      \"method\": \"Identification of RNF167 as Sestrin2 E3 ligase; co-immunoprecipitation of ubiquitinated Sestrin2 with GATOR2; knockout/correction of STAMBPL1; cell-permeable peptide blocking STAMBPL1-Sestrin2 interaction; xenograft tumor assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic KO, epistasis through nutrient signaling, and in vivo xenograft validation in a single rigorous study\",\n      \"pmids\": [\"35114100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF167 ubiquitinates Rab7 GTPase; Rab7 must be in its GTP-bound (active), membrane-anchored form to be accessible for RNF167-mediated ubiquitination; RNF167 activity maintains Rab7 membrane localization and affects endosomal vesicle size; Rab7 ubiquitination by RNF167 is impaired by Charcot-Marie-Tooth Type 2B disease variants.\",\n      \"method\": \"Co-immunoprecipitation; in vitro ubiquitination assays; subcellular fractionation; epifluorescence microscopy; RNF167 knockdown; CMT2B variant analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ubiquitination confirmed, GTP-dependence characterized, fractionation, and disease-variant functional analysis in a single lab\",\n      \"pmids\": [\"35887194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF167 interacts with Tollip via Tollip's C-terminal CUE domain and attaches K33-linked polyubiquitin chains to Tollip at lysine K235; this ubiquitination is required for Tollip to inhibit TNF-α-induced NF-κB and MAPK (JNK) activation, as the Tollip K235R substitution abolishes suppression of these cascades.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays with linkage-type determination; site-directed mutagenesis (K235R); TNF-α stimulation with NF-κB/MAPK readouts\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, K33 linkage determination, functional mutagenesis with defined signaling readouts; single lab\",\n      \"pmids\": [\"37410058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF167 promotes K6-linked polyubiquitination of RIG-I/MDA5 within their CARD domains and K11-linked polyubiquitination within their CTD domains; K6-ubiquitinated RLRs are recognized by the autophagy cargo adaptor p62 and degraded via selective autophagy, while K11-ubiquitinated RLRs are degraded by the proteasome; through this dual mechanism RNF167 negatively regulates RLR-triggered type I interferon signaling.\",\n      \"method\": \"Ubiquitin linkage-specific assays; domain mapping of ubiquitination sites; p62 interaction studies; autophagy and proteasome inhibition experiments; IFN-I signaling readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — linkage-specific ubiquitination assays, domain-level site mapping, identification of p62 as reader, dual pathway degradation dissection with pathway inhibitors, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39994288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF167 forms a heterodimer with RNF13; this RNF13-RNF167 heterodimer interacts with iduronate 2-sulfatase (IDS) and alters IDS glycosylation and maturation differently than either ligase alone; heterodimer formation modifies the lysosomal trafficking of both RNF13 and RNF167.\",\n      \"method\": \"Co-immunoprecipitation; AlphaFold3-guided interaction prediction; glycosylation and maturation assays; subcellular localization analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, Co-IP-based heterodimer identification without full mechanistic reconstitution of the complex\",\n      \"pmids\": [\"bio_10.1101_2025.06.20.660705\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SMAD3 interacts with RNF167 and STAMBPL1 (by co-immunoprecipitation) and stabilizes Sestrin2 protein levels by modulating the balance of RNF167-mediated ubiquitination and STAMBPL1-mediated deubiquitination, thereby regulating mTORC1 activity and gastric cancer cell behaviors.\",\n      \"method\": \"Co-immunoprecipitation; Western blotting; immunofluorescence; SMAD3 overexpression and knockdown in GC cells\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP only for interaction, no direct ubiquitination reconstitution for SMAD3-RNF167 axis\",\n      \"pmids\": [\"40751214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF167 is a transmembrane RING-type E3 ubiquitin ligase resident in endosomes and lysosomes (localization requiring an intact PA domain) that ubiquitinates multiple substrates—including AMPA receptor subunits (via UBE2D1/UBE2N E2s), Arl8B (K141, controlling lysosome positioning), CASTOR1 (K29-linked, activated by AKT-mediated S14 phosphorylation to activate mTORC1), Sestrin2 (promoting GATOR2 interaction to inhibit mTORC1, counteracted by deubiquitinase STAMBPL1), Tollip (K33-linked at K235, enabling suppression of TNF-α/NF-κB/MAPK signaling), RIG-I/MDA5 (K6-linked CARD degradation via selective autophagy/p62 and K11-linked CTD degradation via proteasome to dampen interferon signaling), and Rab7 (requiring GTP-bound membrane-anchored Rab7); it also forms a heterodimer with the related ligase RNF13 that alters lysosomal trafficking of both proteins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF167 is a transmembrane RING-type E3 ubiquitin ligase resident in endosomes and lysosomes that controls membrane-receptor abundance, organelle dynamics, nutrient signaling, and innate immunity through substrate-specific ubiquitination [#0, #2, #3]. Its catalytic activity requires an intact RING domain, while its protease-associated (PA) domain governs endosomal/lysosomal localization; tumor-derived PA mutations leave the enzyme catalytically active but mislocalized and unable to reach substrates [#1]. RNF167 builds ubiquitin chains by partnering with E2 enzymes UBE2D1 and UBE2N, where an initiating E2 primes the substrate and UBE2N elongates the chain, as reconstituted for the AMPA receptor subunit GluA2 to drive activity-dependent reduction of surface AMPA receptors and synaptic currents [#0, #4]. The ligase shapes the endolysosomal system by ubiquitinating Arl8B at K141 to control lysosome positioning and by ubiquitinating GTP-bound, membrane-anchored Rab7 to maintain its membrane localization and regulate endosomal vesicle size [#2, #6]. RNF167 is a node in mTORC1 control, acting bidirectionally: it drives K29-linked degradation of the arginine sensor CASTOR1 (enhanced by AKT-mediated CASTOR1 S14 phosphorylation) to activate mTORC1, and it ubiquitinates Sestrin2 to promote its GATOR2 interaction and inhibit mTORC1, an event reversed by the deubiquitinase STAMBPL1 [#3, #5]. In immune and inflammatory signaling it attaches K33-linked chains to Tollip at K235 to enable suppression of TNF-\\u03b1-induced NF-\\u03baB and MAPK activation, and it dampens type I interferon responses by directing RIG-I/MDA5 to dual degradation routes\\u2014K6-linked CARD ubiquitination read by p62 for selective autophagy and K11-linked CTD ubiquitination for proteasomal turnover [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established RNF167 as a transmembrane RING E3 ligase that acts at the neuronal surface to control synaptic strength, defining its first physiological substrate.\",\n      \"evidence\": \"Transmembrane RING E3 screen with RING-dead mutant and shRNA in hippocampal neurons, surface AMPAR assays, electrophysiology\",\n      \"pmids\": [\"23129617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site on AMPAR subunits not mapped\", \"E2 partners and chain linkage not yet defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Separated the catalytic and targeting modules of RNF167, showing the RING domain is required for ligase activity while the PA domain dictates endosomal localization, and linking PA mutations to cancer-associated mislocalization.\",\n      \"evidence\": \"Tumor mutation analysis with RING and PA domain mutants, in vitro ligase assays, subcellular localization\",\n      \"pmids\": [\"24387786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the PA domain achieves membrane targeting at the molecular level unresolved\", \"Functional consequence of mislocalization on specific substrates not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended RNF167 function to organelle dynamics by identifying Arl8B as a substrate whose K141 ubiquitination controls lysosome positioning and endocytic trafficking.\",\n      \"evidence\": \"BioID substrate screen, in vitro ubiquitination, K141R rescue, lysosome positioning readouts\",\n      \"pmids\": [\"27808481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chain linkage type on Arl8B not specified\", \"Upstream signals regulating this event unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the enzymatic logic of RNF167 chain assembly, showing an initiating E2 primes the substrate and UBE2N elongates the chain, validated for GluA2 and confirmed in neurons.\",\n      \"evidence\": \"In vitro reconstitution with defined E2s, kinetic binding measurements, GluA2 polyubiquitination assay, UBE2N inhibition in neurons\",\n      \"pmids\": [\"33650289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the priming E2 not fully resolved\", \"Whether the same E2 logic applies to all substrates untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected RNF167 to mTORC1 activation by showing AKT-phosphorylated CASTOR1 is degraded via K29-linked ubiquitination, providing an arginine-independent route to mTORC1 activity in cancer.\",\n      \"evidence\": \"Co-IP, K29 linkage-specific ubiquitination assays, S14 phospho-mutagenesis, AKT kinase assay, xenograft models\",\n      \"pmids\": [\"33594058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CASTOR1 turnover occurs at the lysosomal membrane unclear\", \"Counteracting deubiquitinase not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed RNF167 as a bidirectional mTORC1 regulator, ubiquitinating Sestrin2 to promote GATOR2 binding and inhibit mTORC1, opposed by the deubiquitinase STAMBPL1 under leucine control.\",\n      \"evidence\": \"E3 identification, Co-IP of ubiquitinated Sestrin2 with GATOR2, STAMBPL1 KO/correction, blocking peptide, xenografts\",\n      \"pmids\": [\"35114100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How leucine availability is sensed upstream of this axis unclear\", \"Reconciliation of opposing CASTOR1/Sestrin2 effects on mTORC1 not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RNF167 ubiquitinates GTP-bound, membrane-anchored Rab7 to sustain Rab7 membrane localization and regulate endosomal vesicle size, with disease variants impairing the reaction.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, subcellular fractionation, microscopy, CMT2B variant analysis\",\n      \"pmids\": [\"35887194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site and chain linkage on Rab7 not defined\", \"Mechanistic link to Charcot-Marie-Tooth pathology not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed RNF167 in inflammatory signaling control by showing K33-linked ubiquitination of Tollip at K235 is required for suppression of TNF-\\u03b1-induced NF-\\u03baB and MAPK activation.\",\n      \"evidence\": \"Reciprocal Co-IP via Tollip CUE domain, K33 linkage determination, K235R mutagenesis, TNF-\\u03b1-stimulated signaling readouts\",\n      \"pmids\": [\"37410058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector engaged by K33-ubiquitinated Tollip unclear\", \"Physiological setting in vivo not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a dual-pathway mechanism by which RNF167 dampens antiviral interferon signaling, routing RIG-I/MDA5 to autophagy via K6/p62 and to the proteasome via K11.\",\n      \"evidence\": \"Linkage-specific ubiquitination assays, domain-level site mapping, p62 interaction studies, autophagy/proteasome inhibition, IFN-I readouts\",\n      \"pmids\": [\"39994288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger determining K6 versus K11 chain choice unknown\", \"Whether localization at endolysosomes is required for RLR targeting untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed that RNF167 heterodimerizes with RNF13 to co-regulate IDS maturation and the lysosomal trafficking of both ligases, extending RNF167 function into partner-modulated activity.\",\n      \"evidence\": \"Co-IP, AlphaFold3-guided prediction, glycosylation/maturation assays, localization analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.20.660705\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Heterodimer identified by Co-IP without reconstitution of the complex\", \"Catalytic consequence of heterodimerization not directly demonstrated\", \"Whether IDS is a direct substrate unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SMAD3 as an upstream regulator that stabilizes Sestrin2 by tuning the RNF167/STAMBPL1 ubiquitination balance in gastric cancer.\",\n      \"evidence\": \"Co-IP, Western blot, immunofluorescence, SMAD3 gain/loss-of-function in gastric cancer cells\",\n      \"pmids\": [\"40751214\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Interaction shown by Co-IP only without ubiquitination reconstitution for the SMAD3 axis\", \"Whether SMAD3 acts on RNF167 catalysis or substrate access unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF167 selects among its diverse substrates and assembles distinct chain linkages (K6, K11, K29, K33) in different subcellular and signaling contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or E2 engagement\", \"Determinants of linkage-type specificity unknown\", \"Spatial coupling between localization and substrate choice undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 6, 7, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 7, 8]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2, 4, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 5, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\n      \"RNF13-RNF167 heterodimer\"\n    ],\n    \"partners\": [\n      \"UBE2D1\",\n      \"UBE2N\",\n      \"CASTOR1\",\n      \"SESN2\",\n      \"STAMBPL1\",\n      \"TOLLIP\",\n      \"RNF13\",\n      \"RAB7A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}