{"gene":"RNF170","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2011,"finding":"RNF170 is an ER membrane-localized ubiquitin E3 ligase with three predicted transmembrane helices that associates with activated IP3 receptors and mediates their ubiquitination and proteasomal degradation. A substantial proportion of RNF170 constitutively associates with the erlin1/2 (SPFH1/2) complex, which recruits RNF170 to activated IP3 receptors. Depletion of erlin1/2 inhibited RNF170 binding to IP3 receptors, whereas RNF170 depletion did not affect erlin1/2 binding, establishing the epistatic order: erlin1/2 complex binds activated IP3R first, then recruits RNF170 for ubiquitination.","method":"RNA interference knockdown, overexpression of catalytically inactive mutant, co-immunoprecipitation, subcellular fractionation, ubiquitination assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNAi, dominant-negative, Co-IP, fractionation) in a single study with clear epistasis established","pmids":["21610068"],"is_preprint":false},{"year":2015,"finding":"The ADSA-causing point mutation R199C in RNF170 destabilizes the protein by enhancing RNF170 autoubiquitination and proteasomal degradation, mediated by disruption of ionic interactions between charged residues in the transmembrane domains required for stability. CRISPR/Cas9 deletion of RNF170 demonstrated it mediates addition of all ubiquitin conjugates on activated IP3 receptors (monoubiquitin, K48- and K63-linked chains). In ADSA lymphoblasts, platelet-activating factor-induced Ca2+ mobilization was significantly impaired without changes in Ca2+ store content, IP3R levels, or IP3 production, indicating a functional defect at the IP3R locus.","method":"Site-directed mutagenesis, CRISPR/Cas9 knockout, Ca2+ imaging, immunoprecipitation, proteasome inhibitor assays, lymphoblast studies from ADSA patients","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution via mutagenesis, CRISPR KO, patient-derived cells, multiple orthogonal readouts in one study","pmids":["25882839"],"is_preprint":false},{"year":2015,"finding":"Loss of Rnf170 in knockout mice leads to elevated Itpr1 protein levels specifically in cerebellum and spinal cord (but not cerebral cortex), confirming that RNF170 mediates ITPR1 degradation in vivo in a region-specific manner, and that loss of this function recapitulates ADSA-like gait abnormalities and reduced proprioception.","method":"Rnf170 knockout mouse generation, protein blot analysis, behavioral gait analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular/molecular phenotype (elevated IP3R, gait defect), single lab","pmids":["26433933"],"is_preprint":false},{"year":2019,"finding":"RNF170 acts as an E3 ubiquitin ligase for TLR3, binding TLR3 and mediating K48-linked polyubiquitination at K766 in the TIR domain, promoting proteasomal degradation of TLR3 and thereby suppressing TLR3-triggered innate immune signaling (IRF3 and NF-κB activation). Genetic ablation of RNF170 selectively augmented TLR3-triggered innate immune responses both in vitro and in vivo.","method":"Co-immunoprecipitation (TLR3-binding protein pulldown in macrophages), ubiquitination assays (K48-linkage, site-specific mutagenesis at K766), RNF170 knockout cells and mice, innate immune signaling assays","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, site-specific mutagenesis identifying ubiquitination site, KO with defined immune phenotype in vitro and in vivo","pmids":["31076723"],"is_preprint":false},{"year":2019,"finding":"Loss-of-function mutations in RNF170 cause autosomal recessive hereditary spastic paraplegia (HSP) in humans, and functional evaluation in patient fibroblasts and mutant SH-SY5Y cells showed impaired IP3 receptor degradation, confirming that RNF170's E3 ligase activity toward IP3R is required for normal neuronal Ca2+ homeostasis. Gene knockdown in zebrafish recapitulated the HSP phenotype.","method":"Patient fibroblast functional assays, SH-SY5Y cell mutant studies, zebrafish gene knockdown, exome sequencing","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — patient cells and zebrafish model with defined phenotypic readout, moderate evidence from single study","pmids":["31636353"],"is_preprint":false},{"year":2024,"finding":"ERLIN1/2 scaffolds mediate the interaction between full-length TMUB1 and RNF170 on the ER membrane. A luminal N-terminal conserved region in both TMUB1 and RNF170 is required for this interaction, and 3D modelling shows this motif binds the SPFH domain of adjacent ERLIN subunits. Loss of ERLIN scaffolds (double KO) disrupted cholesterol esterification regulation and Golgi morphology, placing RNF170 within an ERLIN-organized functional nanodomain.","method":"Co-immunoprecipitation, omics-based interactome, 3D structural modelling, HeLa double-KO phenotypic characterization, domain mutagenesis","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP with domain mapping and structural modelling, KO phenotype; single lab","pmids":["38782601"],"is_preprint":false},{"year":2025,"finding":"RNF170 (together with RNF149) polyubiquitinates the DEK protein at K349 via K48-linked chains, leading to DEK proteasomal degradation. This ubiquitination was identified by mass spectrometry and functional assays in bronchial epithelial cells.","method":"Mass spectrometry, molecular docking, co-immunoprecipitation, ubiquitination site mutagenesis, functional degradation assays","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — MS identification of ubiquitination site, functional assays; single lab, novel substrate","pmids":["40120540"],"is_preprint":false}],"current_model":"RNF170 is an ER membrane-anchored RING-domain E3 ubiquitin ligase that is recruited to activated IP3 receptors via the erlin1/2 (SPFH1/2) scaffold complex, where it mediates K48- and K63-linked polyubiquitination and monoubiquitination of IP3Rs to drive their proteasomal degradation; it also ubiquitinates TLR3 (K48-linked at K766) and DEK to promote their degradation, and its stability depends on ionic interactions within its transmembrane domains, with loss or mutation causing impaired Ca2+ signaling and neurodegeneration (sensory ataxia, hereditary spastic paraplegia)."},"narrative":{"teleology":[{"year":2011,"claim":"Identification of RNF170 as the E3 ligase responsible for activated IP3R ubiquitination resolved the long-standing question of which enzyme marks IP3Rs for proteasomal degradation, and established that the erlin1/2 complex acts upstream to recruit RNF170 to its substrate.","evidence":"RNAi, dominant-negative overexpression, co-immunoprecipitation, and subcellular fractionation in mammalian cells","pmids":["21610068"],"confidence":"High","gaps":["The ubiquitin chain types deposited by RNF170 on IP3R were not resolved","In vivo physiological consequences of RNF170 loss were unknown","The structural basis of the erlin1/2–RNF170 interaction was undefined"]},{"year":2015,"claim":"Characterization of the ADSA-causing R199C mutation and CRISPR knockout revealed that RNF170 is responsible for all ubiquitin conjugate types on activated IP3Rs (mono, K48, K63), that ionic interactions within its transmembrane domains stabilize the protein, and that loss of RNF170 impairs IP3R-mediated Ca²⁺ mobilization in patient cells — directly linking the enzyme to a human neurodegenerative disease mechanism.","evidence":"Site-directed mutagenesis, CRISPR/Cas9 knockout, Ca²⁺ imaging in ADSA patient lymphoblasts, proteasome inhibitor chase","pmids":["25882839"],"confidence":"High","gaps":["Whether IP3R accumulation alone is sufficient to cause neurodegeneration was not tested","The E2 ubiquitin-conjugating enzyme partnering with RNF170 was not identified"]},{"year":2015,"claim":"An Rnf170 knockout mouse demonstrated region-specific accumulation of Itpr1 in cerebellum and spinal cord (but not cortex), establishing that RNF170 controls IP3R turnover in vivo in the precise neural territories affected in sensory ataxia.","evidence":"Rnf170 knockout mouse, immunoblot of regional brain lysates, gait behavioral analysis","pmids":["26433933"],"confidence":"Medium","gaps":["The basis for tissue-specific IP3R accumulation (e.g., differential erlin expression) was not determined","Electrophysiological or circuit-level consequences in cerebellum were not examined"]},{"year":2019,"claim":"Discovery that RNF170 ubiquitinates TLR3 at K766 via K48-linked chains to promote its proteasomal degradation broadened RNF170's substrate repertoire beyond IP3Rs and established it as a negative regulator of TLR3-mediated innate immunity.","evidence":"Reciprocal co-immunoprecipitation in macrophages, K766 site mutagenesis, RNF170 KO cells and mice with immune signaling readouts","pmids":["31076723"],"confidence":"High","gaps":["Whether erlin1/2 scaffolds are required for TLR3 ubiquitination by RNF170 was not addressed","Physiological immune phenotypes (infection susceptibility) in RNF170 KO mice were not characterized"]},{"year":2019,"claim":"Identification of autosomal recessive loss-of-function RNF170 mutations causing hereditary spastic paraplegia, confirmed by impaired IP3R degradation in patient fibroblasts and phenocopy in zebrafish, established that RNF170 deficiency underlies distinct upper and lower motor neuron disease depending on allelic severity.","evidence":"Patient exome sequencing, fibroblast IP3R degradation assays, zebrafish morpholino knockdown","pmids":["31636353"],"confidence":"Medium","gaps":["The precise threshold of residual RNF170 activity that distinguishes ADSA from HSP is unknown","Rescue experiments restoring RNF170 in patient cells were not reported"]},{"year":2024,"claim":"Mapping of the luminal N-terminal motif in RNF170 (and TMUB1) that binds the SPFH domain of erlin subunits provided the first structural model for how ER membrane E3 ligases are organized within erlin-scaffolded nanodomains, and linked this complex to cholesterol esterification and Golgi morphology.","evidence":"Co-immunoprecipitation, domain mutagenesis, 3D structural modelling, erlin1/2 double-KO HeLa phenotyping","pmids":["38782601"],"confidence":"Medium","gaps":["An experimental high-resolution structure of the erlin–RNF170 interface is lacking","Whether cholesterol-related phenotypes depend specifically on RNF170 catalytic activity was not tested"]},{"year":2025,"claim":"Identification of DEK as a third RNF170 substrate (K48-linked ubiquitination at K349) extended the enzyme's known substrate repertoire to a nuclear chromatin factor, indicating RNF170 functions are not restricted to ER-resident proteins.","evidence":"Mass spectrometry, molecular docking, co-immunoprecipitation and ubiquitination site mutagenesis in bronchial epithelial cells","pmids":["40120540"],"confidence":"Medium","gaps":["DEK is a nuclear protein; the compartment in which RNF170 encounters DEK is unclear","Physiological consequence of DEK degradation by RNF170 beyond bronchial epithelial cells is unknown","Whether RNF170 or RNF149 is the primary E3 for DEK was not delineated"]},{"year":null,"claim":"The cognate E2 enzyme(s) for RNF170, the full structural basis of the erlin–RNF170 complex, and the mechanism by which RNF170 selects among its diverse substrates remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No E2 conjugating enzyme has been identified for RNF170","No high-resolution structure of the erlin1/2–RNF170 complex exists","The substrate selectivity mechanism across IP3R, TLR3, and DEK is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,6]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,3,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4]}],"complexes":["erlin1/2 (SPFH1/SPFH2) complex"],"partners":["ERLIN1","ERLIN2","ITPR1","TLR3","TMUB1","DEK"],"other_free_text":[]},"mechanistic_narrative":"RNF170 is an endoplasmic reticulum membrane-anchored RING-domain E3 ubiquitin ligase that controls the turnover of inositol 1,4,5-trisphosphate receptors (IP3Rs) and additional substrates through proteasomal degradation. RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) scaffold complex, which recruits it to activated IP3Rs; RNF170 then catalyzes monoubiquitination and K48- and K63-linked polyubiquitination of IP3Rs, driving their proteasomal destruction and thereby shaping intracellular Ca²⁺ signaling [PMID:21610068, PMID:25882839]. Beyond IP3R, RNF170 ubiquitinates TLR3 (K48-linked at K766) to promote its degradation and restrain TLR3-triggered innate immune signaling [PMID:31076723], and mediates K48-linked polyubiquitination of the chromatin protein DEK at K349 [PMID:40120540]. Loss-of-function mutations in RNF170 cause autosomal dominant sensory ataxia (ADSA) and autosomal recessive hereditary spastic paraplegia, linked to impaired IP3R degradation and defective Ca²⁺ homeostasis in the cerebellum and spinal cord [PMID:25882839, PMID:26433933, PMID:31636353]."},"prefetch_data":{"uniprot":{"accession":"Q96K19","full_name":"E3 ubiquitin-protein ligase RNF170","aliases":["Putative LAG1-interacting protein","RING finger protein 170","RING-type E3 ubiquitin transferase RNF170"],"length_aa":258,"mass_kda":29.8,"function":"E3 ubiquitin-protein ligase that plays an essential role in stimulus-induced inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) ubiquitination and degradation via the endoplasmic reticulum-associated degradation (ERAD) pathway. Also involved in ITPR1 turnover in resting cells. Selectively inhibits the TLR3-triggered innate immune response by promoting the 'Lys-48'-linked polyubiquitination and degradation of TLR3 (PubMed:31076723)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96K19/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF170","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":[],"url":"https://opencell.sf.czbiohub.org/search/RNF170","total_profiled":1310},"omim":[{"mim_id":"619686","title":"SPASTIC PARAPLEGIA 85, AUTOSOMAL RECESSIVE; SPG85","url":"https://www.omim.org/entry/619686"},{"mim_id":"614649","title":"RING FINGER PROTEIN 170; RNF170","url":"https://www.omim.org/entry/614649"},{"mim_id":"608984","title":"ATAXIA, SENSORY, 1, AUTOSOMAL DOMINANT; SNAX1","url":"https://www.omim.org/entry/608984"},{"mim_id":"270800","title":"SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE; SPG5A","url":"https://www.omim.org/entry/270800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNF170"},"hgnc":{"alias_symbol":["DKFZP564A022","ADSA"],"prev_symbol":["SNAX1"]},"alphafold":{"accession":"Q96K19","domains":[{"cath_id":"3.30.40.10","chopping":"55-170","consensus_level":"high","plddt":84.0727,"start":55,"end":170},{"cath_id":"1.20.5","chopping":"22-50","consensus_level":"medium","plddt":78.8362,"start":22,"end":50},{"cath_id":"1.10.287","chopping":"191-258","consensus_level":"high","plddt":68.7565,"start":191,"end":258}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96K19","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96K19-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96K19-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF170","jax_strain_url":"https://www.jax.org/strain/search?query=RNF170"},"sequence":{"accession":"Q96K19","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96K19.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96K19/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96K19"}},"corpus_meta":[{"pmid":"11913691","id":"PMC_11913691","title":"ADSA Foundation Scholar Award. Formation and physical properties of milk protein gels.","date":"2002","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/11913691","citation_count":178,"is_preprint":false},{"pmid":"10913094","id":"PMC_10913094","title":"An A-factor-dependent extracytoplasmic function sigma factor (sigma(AdsA)) that is essential for morphological development in Streptomyces griseus.","date":"2000","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/10913094","citation_count":94,"is_preprint":false},{"pmid":"21610068","id":"PMC_21610068","title":"RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21610068","citation_count":82,"is_preprint":false},{"pmid":"18349221","id":"PMC_18349221","title":"ADSA Foundation Scholar Award: Possibilities and challenges of exopolysaccharide-producing lactic cultures in dairy foods.","date":"2008","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/18349221","citation_count":51,"is_preprint":false},{"pmid":"31636353","id":"PMC_31636353","title":"Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31636353","citation_count":41,"is_preprint":false},{"pmid":"21115467","id":"PMC_21115467","title":"A mutation in the RNF170 gene causes autosomal dominant sensory ataxia.","date":"2010","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21115467","citation_count":33,"is_preprint":false},{"pmid":"34053756","id":"PMC_34053756","title":"ADSA Foundation Scholar Award: New frontiers in calf and heifer nutrition-From conception to puberty.","date":"2021","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/34053756","citation_count":30,"is_preprint":false},{"pmid":"25882839","id":"PMC_25882839","title":"A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate Receptor-mediated Ca2+ Signaling.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25882839","citation_count":26,"is_preprint":false},{"pmid":"31076723","id":"PMC_31076723","title":"E3 ubiquitin ligase RNF170 inhibits innate immune responses by targeting and degrading TLR3 in murine cells.","date":"2019","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31076723","citation_count":19,"is_preprint":false},{"pmid":"12836921","id":"PMC_12836921","title":"ADSA Foundation Scholar Award--An integrated science-based approach to dairy food safety: Listeria monocytogenes as a model system.","date":"2003","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/12836921","citation_count":19,"is_preprint":false},{"pmid":"26433933","id":"PMC_26433933","title":"Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26433933","citation_count":12,"is_preprint":false},{"pmid":"33165979","id":"PMC_33165979","title":"RNF170-Related Hereditary Spastic Paraplegia: Confirmation by a Novel Mutation.","date":"2020","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/33165979","citation_count":9,"is_preprint":false},{"pmid":"34469621","id":"PMC_34469621","title":"RNF170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement.","date":"2021","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34469621","citation_count":6,"is_preprint":false},{"pmid":"38782601","id":"PMC_38782601","title":"ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/38782601","citation_count":4,"is_preprint":false},{"pmid":"35041108","id":"PMC_35041108","title":"A novel homozygous variant in RNF170 causes hereditary spastic paraplegia: a case report and review of the literature.","date":"2022","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/35041108","citation_count":4,"is_preprint":false},{"pmid":"40120540","id":"PMC_40120540","title":"Eupalinolide B targets DEK and PANoptosis through E3 ubiquitin ligases RNF149 and RNF170 to negatively regulate asthma.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40120540","citation_count":3,"is_preprint":false},{"pmid":"36046950","id":"PMC_36046950","title":"Novel stop-gain RNF170 variation detected in a Chinese family with adolescent-onset hereditary spastic paraplegia.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36046950","citation_count":2,"is_preprint":false},{"pmid":"35400497","id":"PMC_35400497","title":"ADSA Foundation Scholar Award: Materials science approach to the study of mechanical and diffusion properties in cheese.","date":"2022","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/35400497","citation_count":2,"is_preprint":false},{"pmid":"39177409","id":"PMC_39177409","title":"Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy.","date":"2024","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/39177409","citation_count":2,"is_preprint":false},{"pmid":"18197401","id":"PMC_18197401","title":"ADSA-TRIS: a new method to study interfacial phenomena at polymer-aqueous solution interfaces.","date":"2008","source":"Analytical and bioanalytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18197401","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11062,"output_tokens":2127,"usd":0.032545},"stage2":{"model":"claude-opus-4-6","input_tokens":5387,"output_tokens":4948,"usd":0.225953},"total_usd":0.258498,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"RNF170 is an ER membrane-localized ubiquitin E3 ligase with three predicted transmembrane helices that associates with activated IP3 receptors and mediates their ubiquitination and proteasomal degradation. A substantial proportion of RNF170 constitutively associates with the erlin1/2 (SPFH1/2) complex, which recruits RNF170 to activated IP3 receptors. Depletion of erlin1/2 inhibited RNF170 binding to IP3 receptors, whereas RNF170 depletion did not affect erlin1/2 binding, establishing the epistatic order: erlin1/2 complex binds activated IP3R first, then recruits RNF170 for ubiquitination.\",\n      \"method\": \"RNA interference knockdown, overexpression of catalytically inactive mutant, co-immunoprecipitation, subcellular fractionation, ubiquitination assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNAi, dominant-negative, Co-IP, fractionation) in a single study with clear epistasis established\",\n      \"pmids\": [\"21610068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ADSA-causing point mutation R199C in RNF170 destabilizes the protein by enhancing RNF170 autoubiquitination and proteasomal degradation, mediated by disruption of ionic interactions between charged residues in the transmembrane domains required for stability. CRISPR/Cas9 deletion of RNF170 demonstrated it mediates addition of all ubiquitin conjugates on activated IP3 receptors (monoubiquitin, K48- and K63-linked chains). In ADSA lymphoblasts, platelet-activating factor-induced Ca2+ mobilization was significantly impaired without changes in Ca2+ store content, IP3R levels, or IP3 production, indicating a functional defect at the IP3R locus.\",\n      \"method\": \"Site-directed mutagenesis, CRISPR/Cas9 knockout, Ca2+ imaging, immunoprecipitation, proteasome inhibitor assays, lymphoblast studies from ADSA patients\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution via mutagenesis, CRISPR KO, patient-derived cells, multiple orthogonal readouts in one study\",\n      \"pmids\": [\"25882839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Rnf170 in knockout mice leads to elevated Itpr1 protein levels specifically in cerebellum and spinal cord (but not cerebral cortex), confirming that RNF170 mediates ITPR1 degradation in vivo in a region-specific manner, and that loss of this function recapitulates ADSA-like gait abnormalities and reduced proprioception.\",\n      \"method\": \"Rnf170 knockout mouse generation, protein blot analysis, behavioral gait analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular/molecular phenotype (elevated IP3R, gait defect), single lab\",\n      \"pmids\": [\"26433933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RNF170 acts as an E3 ubiquitin ligase for TLR3, binding TLR3 and mediating K48-linked polyubiquitination at K766 in the TIR domain, promoting proteasomal degradation of TLR3 and thereby suppressing TLR3-triggered innate immune signaling (IRF3 and NF-κB activation). Genetic ablation of RNF170 selectively augmented TLR3-triggered innate immune responses both in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (TLR3-binding protein pulldown in macrophages), ubiquitination assays (K48-linkage, site-specific mutagenesis at K766), RNF170 knockout cells and mice, innate immune signaling assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, site-specific mutagenesis identifying ubiquitination site, KO with defined immune phenotype in vitro and in vivo\",\n      \"pmids\": [\"31076723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function mutations in RNF170 cause autosomal recessive hereditary spastic paraplegia (HSP) in humans, and functional evaluation in patient fibroblasts and mutant SH-SY5Y cells showed impaired IP3 receptor degradation, confirming that RNF170's E3 ligase activity toward IP3R is required for normal neuronal Ca2+ homeostasis. Gene knockdown in zebrafish recapitulated the HSP phenotype.\",\n      \"method\": \"Patient fibroblast functional assays, SH-SY5Y cell mutant studies, zebrafish gene knockdown, exome sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient cells and zebrafish model with defined phenotypic readout, moderate evidence from single study\",\n      \"pmids\": [\"31636353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ERLIN1/2 scaffolds mediate the interaction between full-length TMUB1 and RNF170 on the ER membrane. A luminal N-terminal conserved region in both TMUB1 and RNF170 is required for this interaction, and 3D modelling shows this motif binds the SPFH domain of adjacent ERLIN subunits. Loss of ERLIN scaffolds (double KO) disrupted cholesterol esterification regulation and Golgi morphology, placing RNF170 within an ERLIN-organized functional nanodomain.\",\n      \"method\": \"Co-immunoprecipitation, omics-based interactome, 3D structural modelling, HeLa double-KO phenotypic characterization, domain mutagenesis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP with domain mapping and structural modelling, KO phenotype; single lab\",\n      \"pmids\": [\"38782601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF170 (together with RNF149) polyubiquitinates the DEK protein at K349 via K48-linked chains, leading to DEK proteasomal degradation. This ubiquitination was identified by mass spectrometry and functional assays in bronchial epithelial cells.\",\n      \"method\": \"Mass spectrometry, molecular docking, co-immunoprecipitation, ubiquitination site mutagenesis, functional degradation assays\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS identification of ubiquitination site, functional assays; single lab, novel substrate\",\n      \"pmids\": [\"40120540\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF170 is an ER membrane-anchored RING-domain E3 ubiquitin ligase that is recruited to activated IP3 receptors via the erlin1/2 (SPFH1/2) scaffold complex, where it mediates K48- and K63-linked polyubiquitination and monoubiquitination of IP3Rs to drive their proteasomal degradation; it also ubiquitinates TLR3 (K48-linked at K766) and DEK to promote their degradation, and its stability depends on ionic interactions within its transmembrane domains, with loss or mutation causing impaired Ca2+ signaling and neurodegeneration (sensory ataxia, hereditary spastic paraplegia).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RNF170 is an endoplasmic reticulum membrane-anchored RING-domain E3 ubiquitin ligase that controls the turnover of inositol 1,4,5-trisphosphate receptors (IP3Rs) and additional substrates through proteasomal degradation. RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) scaffold complex, which recruits it to activated IP3Rs; RNF170 then catalyzes monoubiquitination and K48- and K63-linked polyubiquitination of IP3Rs, driving their proteasomal destruction and thereby shaping intracellular Ca²⁺ signaling [PMID:21610068, PMID:25882839]. Beyond IP3R, RNF170 ubiquitinates TLR3 (K48-linked at K766) to promote its degradation and restrain TLR3-triggered innate immune signaling [PMID:31076723], and mediates K48-linked polyubiquitination of the chromatin protein DEK at K349 [PMID:40120540]. Loss-of-function mutations in RNF170 cause autosomal dominant sensory ataxia (ADSA) and autosomal recessive hereditary spastic paraplegia, linked to impaired IP3R degradation and defective Ca²⁺ homeostasis in the cerebellum and spinal cord [PMID:25882839, PMID:26433933, PMID:31636353].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of RNF170 as the E3 ligase responsible for activated IP3R ubiquitination resolved the long-standing question of which enzyme marks IP3Rs for proteasomal degradation, and established that the erlin1/2 complex acts upstream to recruit RNF170 to its substrate.\",\n      \"evidence\": \"RNAi, dominant-negative overexpression, co-immunoprecipitation, and subcellular fractionation in mammalian cells\",\n      \"pmids\": [\"21610068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The ubiquitin chain types deposited by RNF170 on IP3R were not resolved\",\n        \"In vivo physiological consequences of RNF170 loss were unknown\",\n        \"The structural basis of the erlin1/2–RNF170 interaction was undefined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Characterization of the ADSA-causing R199C mutation and CRISPR knockout revealed that RNF170 is responsible for all ubiquitin conjugate types on activated IP3Rs (mono, K48, K63), that ionic interactions within its transmembrane domains stabilize the protein, and that loss of RNF170 impairs IP3R-mediated Ca²⁺ mobilization in patient cells — directly linking the enzyme to a human neurodegenerative disease mechanism.\",\n      \"evidence\": \"Site-directed mutagenesis, CRISPR/Cas9 knockout, Ca²⁺ imaging in ADSA patient lymphoblasts, proteasome inhibitor chase\",\n      \"pmids\": [\"25882839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IP3R accumulation alone is sufficient to cause neurodegeneration was not tested\",\n        \"The E2 ubiquitin-conjugating enzyme partnering with RNF170 was not identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An Rnf170 knockout mouse demonstrated region-specific accumulation of Itpr1 in cerebellum and spinal cord (but not cortex), establishing that RNF170 controls IP3R turnover in vivo in the precise neural territories affected in sensory ataxia.\",\n      \"evidence\": \"Rnf170 knockout mouse, immunoblot of regional brain lysates, gait behavioral analysis\",\n      \"pmids\": [\"26433933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The basis for tissue-specific IP3R accumulation (e.g., differential erlin expression) was not determined\",\n        \"Electrophysiological or circuit-level consequences in cerebellum were not examined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that RNF170 ubiquitinates TLR3 at K766 via K48-linked chains to promote its proteasomal degradation broadened RNF170's substrate repertoire beyond IP3Rs and established it as a negative regulator of TLR3-mediated innate immunity.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation in macrophages, K766 site mutagenesis, RNF170 KO cells and mice with immune signaling readouts\",\n      \"pmids\": [\"31076723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether erlin1/2 scaffolds are required for TLR3 ubiquitination by RNF170 was not addressed\",\n        \"Physiological immune phenotypes (infection susceptibility) in RNF170 KO mice were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of autosomal recessive loss-of-function RNF170 mutations causing hereditary spastic paraplegia, confirmed by impaired IP3R degradation in patient fibroblasts and phenocopy in zebrafish, established that RNF170 deficiency underlies distinct upper and lower motor neuron disease depending on allelic severity.\",\n      \"evidence\": \"Patient exome sequencing, fibroblast IP3R degradation assays, zebrafish morpholino knockdown\",\n      \"pmids\": [\"31636353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The precise threshold of residual RNF170 activity that distinguishes ADSA from HSP is unknown\",\n        \"Rescue experiments restoring RNF170 in patient cells were not reported\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapping of the luminal N-terminal motif in RNF170 (and TMUB1) that binds the SPFH domain of erlin subunits provided the first structural model for how ER membrane E3 ligases are organized within erlin-scaffolded nanodomains, and linked this complex to cholesterol esterification and Golgi morphology.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mutagenesis, 3D structural modelling, erlin1/2 double-KO HeLa phenotyping\",\n      \"pmids\": [\"38782601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"An experimental high-resolution structure of the erlin–RNF170 interface is lacking\",\n        \"Whether cholesterol-related phenotypes depend specifically on RNF170 catalytic activity was not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of DEK as a third RNF170 substrate (K48-linked ubiquitination at K349) extended the enzyme's known substrate repertoire to a nuclear chromatin factor, indicating RNF170 functions are not restricted to ER-resident proteins.\",\n      \"evidence\": \"Mass spectrometry, molecular docking, co-immunoprecipitation and ubiquitination site mutagenesis in bronchial epithelial cells\",\n      \"pmids\": [\"40120540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"DEK is a nuclear protein; the compartment in which RNF170 encounters DEK is unclear\",\n        \"Physiological consequence of DEK degradation by RNF170 beyond bronchial epithelial cells is unknown\",\n        \"Whether RNF170 or RNF149 is the primary E3 for DEK was not delineated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cognate E2 enzyme(s) for RNF170, the full structural basis of the erlin–RNF170 complex, and the mechanism by which RNF170 selects among its diverse substrates remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No E2 conjugating enzyme has been identified for RNF170\",\n        \"No high-resolution structure of the erlin1/2–RNF170 complex exists\",\n        \"The substrate selectivity mechanism across IP3R, TLR3, and DEK is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0392499\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\n      \"erlin1/2 (SPFH1/SPFH2) complex\"\n    ],\n    \"partners\": [\n      \"ERLIN1\",\n      \"ERLIN2\",\n      \"ITPR1\",\n      \"TLR3\",\n      \"TMUB1\",\n      \"DEK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I made an error with the pathway term_id. Let me fix:\n\n```json\n{\n  \"mechanistic_narrative\": \"RNF170 is an endoplasmic reticulum membrane-anchored RING-domain E3 ubiquitin ligase that controls the turnover of inositol 1,4,5-trisphosphate receptors (IP3Rs) and additional substrates through proteasomal degradation. RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) scaffold complex, which recruits it to activated IP3Rs; RNF170 then catalyzes monoubiquitination and K48- and K63-linked polyubiquitination of IP3Rs, driving their proteasomal destruction and thereby shaping intracellular Ca²⁺ signaling [PMID:21610068, PMID:25882839]. Beyond IP3R, RNF170 ubiquitinates TLR3 (K48-linked at K766) to promote its degradation and restrain TLR3-triggered innate immune signaling [PMID:31076723], and mediates K48-linked polyubiquitination of the chromatin protein DEK at K349 [PMID:40120540]. Loss-of-function mutations in RNF170 cause autosomal dominant sensory ataxia (ADSA) and autosomal recessive hereditary spastic paraplegia, linked to impaired IP3R degradation and defective Ca²⁺ homeostasis in the cerebellum and spinal cord [PMID:25882839, PMID:26433933, PMID:31636353].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of RNF170 as the E3 ligase responsible for activated IP3R ubiquitination resolved the long-standing question of which enzyme marks IP3Rs for proteasomal degradation, and established that the erlin1/2 complex acts upstream to recruit RNF170 to its substrate.\",\n      \"evidence\": \"RNAi, dominant-negative overexpression, co-immunoprecipitation, and subcellular fractionation in mammalian cells\",\n      \"pmids\": [\"21610068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The ubiquitin chain types deposited by RNF170 on IP3R were not resolved\",\n        \"In vivo physiological consequences of RNF170 loss were unknown\",\n        \"The structural basis of the erlin1/2–RNF170 interaction was undefined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Characterization of the ADSA-causing R199C mutation and CRISPR knockout revealed that RNF170 is responsible for all ubiquitin conjugate types on activated IP3Rs (mono, K48, K63), that ionic interactions within its transmembrane domains stabilize the protein, and that loss of RNF170 impairs IP3R-mediated Ca²⁺ mobilization in patient cells — directly linking the enzyme to a human neurodegenerative disease mechanism.\",\n      \"evidence\": \"Site-directed mutagenesis, CRISPR/Cas9 knockout, Ca²⁺ imaging in ADSA patient lymphoblasts, proteasome inhibitor chase\",\n      \"pmids\": [\"25882839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IP3R accumulation alone is sufficient to cause neurodegeneration was not tested\",\n        \"The E2 ubiquitin-conjugating enzyme partnering with RNF170 was not identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An Rnf170 knockout mouse demonstrated region-specific accumulation of Itpr1 in cerebellum and spinal cord (but not cortex), establishing that RNF170 controls IP3R turnover in vivo in the precise neural territories affected in sensory ataxia.\",\n      \"evidence\": \"Rnf170 knockout mouse, immunoblot of regional brain lysates, gait behavioral analysis\",\n      \"pmids\": [\"26433933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The basis for tissue-specific IP3R accumulation (e.g., differential erlin expression) was not determined\",\n        \"Electrophysiological or circuit-level consequences in cerebellum were not examined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that RNF170 ubiquitinates TLR3 at K766 via K48-linked chains to promote its proteasomal degradation broadened RNF170's substrate repertoire beyond IP3Rs and established it as a negative regulator of TLR3-mediated innate immunity.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation in macrophages, K766 site mutagenesis, RNF170 KO cells and mice with immune signaling readouts\",\n      \"pmids\": [\"31076723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether erlin1/2 scaffolds are required for TLR3 ubiquitination by RNF170 was not addressed\",\n        \"Physiological immune phenotypes (infection susceptibility) in RNF170 KO mice were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of autosomal recessive loss-of-function RNF170 mutations causing hereditary spastic paraplegia, confirmed by impaired IP3R degradation in patient fibroblasts and phenocopy in zebrafish, established that RNF170 deficiency underlies distinct upper and lower motor neuron disease depending on allelic severity.\",\n      \"evidence\": \"Patient exome sequencing, fibroblast IP3R degradation assays, zebrafish morpholino knockdown\",\n      \"pmids\": [\"31636353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The precise threshold of residual RNF170 activity that distinguishes ADSA from HSP is unknown\",\n        \"Rescue experiments restoring RNF170 in patient cells were not reported\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapping of the luminal N-terminal motif in RNF170 (and TMUB1) that binds the SPFH domain of erlin subunits provided the first structural model for how ER membrane E3 ligases are organized within erlin-scaffolded nanodomains, and linked this complex to cholesterol esterification and Golgi morphology.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mutagenesis, 3D structural modelling, erlin1/2 double-KO HeLa phenotyping\",\n      \"pmids\": [\"38782601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"An experimental high-resolution structure of the erlin–RNF170 interface is lacking\",\n        \"Whether cholesterol-related phenotypes depend specifically on RNF170 catalytic activity was not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of DEK as a third RNF170 substrate (K48-linked ubiquitination at K349) extended the enzyme's known substrate repertoire to a nuclear chromatin factor, indicating RNF170 functions are not restricted to ER-resident proteins.\",\n      \"evidence\": \"Mass spectrometry, molecular docking, co-immunoprecipitation and ubiquitination site mutagenesis in bronchial epithelial cells\",\n      \"pmids\": [\"40120540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"DEK is a nuclear protein; the compartment in which RNF170 encounters DEK is unclear\",\n        \"Physiological consequence of DEK degradation by RNF170 beyond bronchial epithelial cells is unknown\",\n        \"Whether RNF170 or RNF149 is the primary E3 for DEK was not delineated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cognate E2 enzyme(s) for RNF170, the full structural basis of the erlin–RNF170 complex, and the mechanism by which RNF170 selects among its diverse substrates remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No E2 conjugating enzyme has been identified for RNF170\",\n        \"No high-resolution structure of the erlin1/2–RNF170 complex exists\",\n        \"The substrate selectivity mechanism across IP3R, TLR3, and DEK is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\n      \"erlin1/2 (SPFH1/SPFH2) complex\"\n    ],\n    \"partners\": [\n      \"ERLIN1\",\n      \"ERLIN2\",\n      \"ITPR1\",\n      \"TLR3\",\n      \"TMUB1\",\n      \"DEK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}