{"gene":"RNF112","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2025,"finding":"RNF112 (ZNF179) is a dynamin-like large GTPase with a crystal structure revealing a GTPase domain (GD) and three-helical middle domain (MD). In the nucleotide-free (apo) state, monomeric RNF112 adopts a self-restraint conformation where the proximal end of the MD docks to a groove in the GD. At the GTP hydrolysis transition state, the MD is released and the protein forms an intertwined homodimer. Engineered RNF112 fused with C-terminal elements of ATL1 or yeast Sac1p transmembrane domains relocates to the endoplasmic reticulum and mediates membrane remodeling, demonstrating latent membrane-remodeling capacity.","method":"Crystal structure determination at different nucleotide-loading states; engineered chimeric constructs with ER-targeting domains; functional membrane remodeling assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with multiple nucleotide states plus functional chimera membrane-remodeling assay in single rigorous study","pmids":["40198702"],"is_preprint":false},{"year":2018,"finding":"RNF112 (Znf179) functions as a RING-domain E3 ubiquitin ligase that autoubiquitinates, regulates 26S proteasome activity by modulating 19S/20S proteasome subunit protein levels, directly interacts with TDP-43, and mediates polyubiquitination of TDP-43 both in vitro and in vivo, accelerating TDP-43 turnover and reducing insoluble TDP-43 aggregates. Knockout of Znf179 in mouse brain results in accumulation of insoluble TDP-43 and cytosolic TDP-43 inclusions in cortex, hippocampus, and midbrain.","method":"In vitro and in vivo ubiquitination assay; co-immunoprecipitation followed by mass spectrometry to identify TDP-43 as substrate; Znf179 knockout mouse model with biochemical fractionation","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of E3 ligase activity, reciprocal Co-IP/MS substrate identification, and in vivo KO model with defined molecular phenotype, multiple orthogonal methods","pmids":["30404641"],"is_preprint":false},{"year":2023,"finding":"RNF112 directly ubiquitinates FOXM1 in gastric cancer cells, leading to decreased FOXM1 protein levels and suppressed FOXM1 transcriptional network, thereby inhibiting gastric cancer cell proliferation and invasion. The small-molecule compound RCM-1 enhances the RNF112–FOXM1 interaction and promotes FOXM1 ubiquitination.","method":"siRNA E3 ligase library screen; co-immunoprecipitation; in vitro/in vivo ubiquitination assay; RNF112 knockdown/overexpression with proliferation and invasion readouts; xenograft mouse model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — E3 ligase activity confirmed by ubiquitination assay, substrate identified by Co-IP, functional rescue in vitro and in vivo, multiple orthogonal methods","pmids":["37288663"],"is_preprint":false},{"year":2025,"finding":"RNF112 directly interacts with the MB II domain of c-Myc through its N-terminal zinc finger motif, and its catalytic site C97 facilitates K48-linked polyubiquitination of K389 on c-Myc, targeting c-Myc for proteasomal degradation and thereby suppressing proliferation, migration, and lipid synthesis (via ACLY) in bladder cancer cells.","method":"Co-immunoprecipitation; domain-mapping experiments; ubiquitination assay with catalytic-site (C97) mutant; K389 mutation on c-Myc; rescue with c-Myc or ACLY re-expression; in vivo xenograft model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — active-site mutagenesis (C97), substrate lysine mapping (K389), linkage specificity (K48), domain interaction mapping, and in vivo rescue, multiple orthogonal methods","pmids":["40178292"],"is_preprint":false},{"year":2025,"finding":"RNF112 promotes ubiquitination and degradation of NAA40 through its E3 ubiquitin ligase activity in colorectal cancer. KLF4 acts as an upstream transcriptional regulator of RNF112 by binding its promoter. Overexpression of NAA40 reverses the anti-tumor effects of RNF112 overexpression, placing RNF112 upstream of NAA40 in CRC.","method":"RNF112 overexpression/knockdown in CRC cells and xenograft; co-immunoprecipitation; ubiquitination assay; chromatin-based KLF4 promoter binding assay; NAA40 rescue experiment","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination assay with rescue, single lab, multiple but not fully orthogonal methods","pmids":["39757327"],"is_preprint":false},{"year":2026,"finding":"RNF112 promotes ubiquitination and degradation of FOXM1 (Foxm1) in cervical cancer, reducing tumor proliferation and alleviating immunosuppression in the tumor microenvironment by protecting T lymphocytes from oxidative stress-induced mitochondrial dysfunction and ferroptosis.","method":"RNF112 knockdown (shRNA) and overexpression; xenograft mouse model; co-culture system of cancer cells with T lymphocytes; ubiquitination assay; Foxm1 inhibition rescue experiment","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assay and functional rescue in vitro and in vivo, single lab","pmids":["42180965"],"is_preprint":false},{"year":2018,"finding":"Znf179 (RNF112) is acetylated on specific lysine residues; oxidative stress induces dissociation of a Znf179–HDAC1/HDAC6 complex, increasing Znf179 acetylation. Hyperacetylated Znf179 forms a transcriptional complex with Sp1 and promotes antioxidant gene expression. HDAC inhibition by SAHA further increases Znf179 acetylation and enhances this protective response.","method":"Immunoprecipitation with acetyl-lysine antibodies; co-immunoprecipitation of Znf179 with HDAC1/HDAC6; SAHA treatment; bioinformatics sequence alignment; reporter assays for antioxidant gene expression","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP for HDAC interaction, acetylation confirmed by two antibodies, functional antioxidant gene readout, single lab","pmids":["30121389"],"is_preprint":false},{"year":2013,"finding":"Znf179 (RNF112) interacts with PLZF (promyelocytic leukemia zinc finger protein); the first two zinc fingers of PLZF are critical for this interaction. Co-expression of PLZF causes Znf179 to relocalize from cytoplasm to nucleus. Znf179 also increases PLZF protein abundance.","method":"Yeast two-hybrid screen; co-immunoprecipitation; domain-deletion mapping; fluorescence microscopy for subcellular localization; Western blot for protein expression","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP for binding, domain mapping, and localization experiment; single lab","pmids":["24359566"],"is_preprint":false},{"year":2011,"finding":"Znf179 (RNF112) is required for neuronal differentiation of P19 embryonal carcinoma cells and cerebellar granule cells. Znf179 knockdown reduces G0/G1 cell-cycle arrest, increases BrdU incorporation, and decreases levels of p35 (neuronal Cdk5 activator) and p27 (CDK inhibitor), linking Znf179 to cell cycle exit as a prerequisite for neuronal differentiation.","method":"RNA interference knockdown; flow cytometry for cell cycle analysis; BrdU incorporation assay; microarray gene expression profiling; Western blot for p35 and p27; primary cerebellar granule cell culture","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype (cell cycle exit) and molecular readouts (p35, p27), multiple orthogonal assays, single lab","pmids":["21566658"],"is_preprint":false},{"year":2017,"finding":"Znf179 (RNF112) overexpression induces differentiation of primary glioblastoma multiforme cells, accompanied by elevated GFAP expression and upregulation of p53, p21, and p27, causing G0/G1 cell-cycle arrest.","method":"Znf179 overexpression in primary GBM cells; flow cytometry for cell cycle; Western blot for p53, p21, p27, GFAP; immunostaining","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — overexpression with mechanistic molecular readouts (p53/p21/p27), single lab, multiple methods","pmids":["28684796"],"is_preprint":false},{"year":2018,"finding":"Rnf112 knockout in mice exacerbates brain injury after intracerebral hemorrhage, associated with upregulation of TLR-4, MyD88, and phosphorylation of IKKα, IκBα, and NF-κB, indicating that Rnf112 suppresses the TLR-4/NF-κB inflammatory pathway. Conversely, Rnf112 overexpression attenuates ICH-induced brain injury by inhibiting this pathway.","method":"Rnf112 knockout mouse model with ICH induction; brain water content and neurological deficit scoring; Western blot for TLR-4/NF-κB pathway components; cytokine measurement; Rnf112 overexpression in LPS-stimulated glial cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined phenotype and molecular pathway readout, overexpression rescue, single lab","pmids":["30454900"],"is_preprint":false},{"year":2020,"finding":"Purα binds directly to the Znf179 (RNF112) promoter and is required for Znf179 transcriptional induction during neuronal differentiation. Overexpression of Purα increases Znf179 expression in neuronal-differentiated P19 cells, and concurrent expression of Purα and Znf179 occurs during neuronal differentiation.","method":"DAPA (DNA affinity precipitation assay) for direct Purα–Znf179 promoter binding; Purα overexpression with Znf179 expression readout; co-expression analysis during P19 differentiation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — DAPA for direct promoter binding, functional overexpression experiment, single lab","pmids":["33333713"],"is_preprint":false},{"year":1997,"finding":"BFP (brain finger protein, RNF112/ZNF179) is a novel RING finger protein predominantly expressed in the brain and induced during retinoic acid-mediated neural differentiation of P19 embryonal carcinoma cells, indicating a role in neural cell regulation.","method":"Northern blot for tissue expression; Western blot with anti-BFP antibody; retinoic acid-induced P19 differentiation model","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression-level observation during differentiation with antibody detection, no direct functional mechanism established","pmids":["9367872"],"is_preprint":false},{"year":1998,"finding":"Mouse Bfp (RNF112) protein is detected predominantly in the nucleus, with some cytoplasmic localization, in primary neonatal brain cultures containing both neurons and glial cells, as determined by immunohistochemistry.","method":"Immunohistochemistry and in situ hybridization in mouse brain sections and primary neonatal brain cultures","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — subcellular localization established by immunohistochemistry in fixed cells, no functional consequence linked","pmids":["9806830"],"is_preprint":false}],"current_model":"RNF112 (ZNF179/BFP) is a brain-enriched RING-domain E3 ubiquitin ligase and dynamin-like large GTPase whose crystal structure reveals a self-restrained monomer that dimerizes upon GTP hydrolysis and can mediate membrane remodeling when targeted to the ER; as an E3 ligase, it ubiquitinates substrates including TDP-43, FOXM1, c-Myc, and NAA40 to promote their proteasomal degradation, thereby suppressing cancer progression and neurodegeneration, while also functioning in neuronal differentiation and cell cycle exit through p27/p35/p53 pathways, and being regulated post-translationally by HDAC1/6-dependent acetylation and transcriptionally by Purα and KLF4."},"narrative":{"mechanistic_narrative":"RNF112 (ZNF179/BFP) is a brain-enriched RING-domain E3 ubiquitin ligase that drives neuronal differentiation and acts as a tumor suppressor by directing substrates to proteasomal degradation [PMID:30404641, PMID:37288663, PMID:40178292]. Crystallographic analysis defines RNF112 as a dynamin-like large GTPase whose GTPase domain (GD) and three-helical middle domain (MD) adopt a self-restrained monomeric conformation in the apo state; at the GTP hydrolysis transition state the MD is released to form an intertwined homodimer, and ER-targeted chimeras reveal latent membrane-remodeling capacity [PMID:40198702]. As an E3 ligase, RNF112 autoubiquitinates and uses its catalytic RING cysteine (C97) to assemble K48-linked polyubiquitin chains on its targets: it polyubiquitinates TDP-43 to accelerate turnover and prevent insoluble cytosolic inclusions in brain [PMID:30404641], and degrades the oncogenic transcription factors FOXM1 and c-Myc as well as NAA40, thereby suppressing proliferation, invasion, and lipid synthesis across gastric, bladder, cervical, and colorectal cancers [PMID:37288663, PMID:40178292, PMID:39757327, PMID:42180965]. In neural development, RNF112 promotes cell-cycle exit required for differentiation, acting through p35/p27 in embryonal carcinoma and cerebellar granule cells and through p53/p21/p27 in glioblastoma cells [PMID:21566658, PMID:28684796]. RNF112 expression is transcriptionally induced by Purα and KLF4 [PMID:33333713, PMID:39757327], and its activity is tuned post-translationally by oxidative-stress-induced dissociation from an HDAC1/HDAC6 complex, leading to hyperacetylation and Sp1-dependent antioxidant gene expression [PMID:30121389].","teleology":[{"year":1997,"claim":"Established RNF112 as a brain-predominant RING finger protein whose expression is induced during neural differentiation, framing it as a candidate regulator of neural cell fate.","evidence":"Northern/Western blot tissue profiling and retinoic acid-induced P19 differentiation","pmids":["9367872"],"confidence":"Low","gaps":["Expression correlation only, no direct functional mechanism established","Did not test E3 ligase activity","No substrate identified"]},{"year":1998,"claim":"Determined RNF112 subcellular distribution as predominantly nuclear with cytoplasmic presence in brain, providing baseline localization for later functional work.","evidence":"Immunohistochemistry and in situ hybridization in mouse brain and primary neonatal cultures","pmids":["9806830"],"confidence":"Low","gaps":["Static localization without functional consequence","Did not resolve what governs nuclear vs cytoplasmic partitioning"]},{"year":2011,"claim":"Showed RNF112 is required for neuronal differentiation by enforcing G0/G1 cell-cycle exit, mechanistically linking it to the p35/p27 axis.","evidence":"RNAi knockdown with cell-cycle/BrdU analysis and p35/p27 Western blot in P19 and cerebellar granule cells","pmids":["21566658"],"confidence":"Medium","gaps":["Did not establish whether RNF112 acts on p35/p27 enzymatically or transcriptionally","Single lab"]},{"year":2013,"claim":"Identified PLZF as an RNF112 partner that drives its cytoplasm-to-nucleus relocalization, beginning to define RNF112's protein-interaction landscape.","evidence":"Yeast two-hybrid, Co-IP, domain mapping, and fluorescence localization","pmids":["24359566"],"confidence":"Medium","gaps":["Did not test whether PLZF is a ubiquitination substrate","Functional consequence of relocalization unresolved"]},{"year":2017,"claim":"Extended the differentiation/cell-cycle-exit role to glioblastoma via a distinct p53/p21/p27 readout, suggesting tumor-suppressive differentiation activity.","evidence":"RNF112 overexpression in primary GBM cells with cell-cycle and p53/p21/p27/GFAP analysis","pmids":["28684796"],"confidence":"Medium","gaps":["Did not connect cell-cycle effects to direct ubiquitination targets","Overexpression only"]},{"year":2018,"claim":"Defined RNF112 as a bona fide E3 ligase that ubiquitinates TDP-43 to suppress aggregation in vivo, establishing its mechanistic role in proteostasis and neurodegeneration.","evidence":"In vitro/in vivo ubiquitination assays, Co-IP/MS substrate identification, and Znf179 knockout mouse with biochemical fractionation","pmids":["30404641"],"confidence":"High","gaps":["Did not map the ubiquitinated lysines on TDP-43","Relationship between proteasome modulation and direct substrate ubiquitination not fully resolved"]},{"year":2018,"claim":"Revealed post-translational control of RNF112 by oxidative-stress-regulated acetylation, coupling redox state to an antioxidant transcriptional response via Sp1.","evidence":"Acetyl-lysine IP, reciprocal Co-IP with HDAC1/HDAC6, SAHA treatment, and antioxidant reporter assays","pmids":["30121389"],"confidence":"Medium","gaps":["Did not link acetylation state to E3 ligase activity","Single lab"]},{"year":2018,"claim":"Showed RNF112 suppresses TLR-4/NF-κB inflammatory signaling in brain injury, broadening its protective role beyond proteostasis.","evidence":"Rnf112 knockout mouse intracerebral hemorrhage model with NF-κB pathway Western blots and overexpression rescue","pmids":["30454900"],"confidence":"Medium","gaps":["Mechanistic link between RNF112 and TLR-4/NF-κB components not defined (no direct substrate)","Single lab"]},{"year":2020,"claim":"Identified Purα as a direct transcriptional activator of RNF112 during neuronal differentiation, defining an upstream input to its expression.","evidence":"DNA affinity precipitation assay for promoter binding and Purα overexpression in differentiating P19 cells","pmids":["33333713"],"confidence":"Medium","gaps":["Did not establish chromatin occupancy in vivo","Single lab"]},{"year":2023,"claim":"Demonstrated RNF112 directly ubiquitinates FOXM1 to inhibit gastric cancer proliferation/invasion, establishing it as a druggable tumor suppressor (via RCM-1).","evidence":"siRNA E3 ligase screen, Co-IP, in vitro/in vivo ubiquitination, and xenograft model","pmids":["37288663"],"confidence":"High","gaps":["Did not map ubiquitinated FOXM1 lysines or linkage type","RCM-1 mechanism of interaction enhancement not structurally resolved"]},{"year":2025,"claim":"Provided high-resolution mechanism for c-Myc degradation, mapping the N-terminal zinc finger interaction with MB II, catalytic C97, and K48-linked ubiquitination of K389.","evidence":"Co-IP, domain/active-site (C97) and substrate-lysine (K389) mutagenesis, linkage analysis, and xenograft rescue in bladder cancer","pmids":["40178292"],"confidence":"High","gaps":["Did not address whether the same residues mediate other substrate interactions","Did not connect to the GTPase activity"]},{"year":2025,"claim":"Resolved the structural basis of RNF112 as a self-restrained dynamin-like GTPase that dimerizes upon hydrolysis and has latent membrane-remodeling capacity.","evidence":"Crystal structures at multiple nucleotide states plus ER-targeted chimera membrane-remodeling assays","pmids":["40198702"],"confidence":"High","gaps":["Native membrane substrate/physiological membrane target unknown","Relationship between GTPase cycle and E3 ligase activity unresolved"]},{"year":2025,"claim":"Placed RNF112 in a KLF4→RNF112⊣NAA40 axis in colorectal cancer, identifying both an upstream activator and a new degradation substrate.","evidence":"Co-IP, ubiquitination assay, KLF4 promoter-binding assay, and NAA40 rescue in CRC cells and xenografts","pmids":["39757327"],"confidence":"Medium","gaps":["NAA40 ubiquitination lysines and linkage not mapped","Single lab"]},{"year":2026,"claim":"Extended FOXM1 degradation to cervical cancer with an immunological consequence, linking RNF112 to protection of T lymphocytes from ferroptosis in the tumor microenvironment.","evidence":"shRNA/overexpression, xenograft, cancer-T cell co-culture, ubiquitination assay, and Foxm1 inhibition rescue","pmids":["42180965"],"confidence":"Medium","gaps":["Direct vs indirect effect on T-cell ferroptosis not fully separated","Single lab"]},{"year":null,"claim":"How the dynamin-like GTPase cycle and membrane-remodeling capacity integrate with the E3 ligase activity, and whether they operate in the same physiological pathway, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No physiological membrane substrate identified","Coupling between nucleotide-dependent dimerization and substrate ubiquitination unknown","Unified model linking neuronal, tumor-suppressive, and membrane functions absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,4]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,13]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9]}],"complexes":[],"partners":["TDP-43","FOXM1","MYC","NAA40","PLZF","HDAC1","HDAC6","SP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULX5","full_name":"RING finger protein 112","aliases":["Brain finger protein","Zinc finger protein 179"],"length_aa":631,"mass_kda":68.3,"function":"E3 ubiquitin-protein ligase that plays an important role in neuronal differentiation, including neurogenesis and gliogenesis, during brain development. During embryonic development initiates neuronal differentiation by inducing cell cycle arrest at the G0/G1 phase through up-regulation of cell-cycle regulatory proteins (PubMed:28684796). Plays a role not only in the fetal period during the development of the nervous system, but also in the adult brain, where it is involved in the maintenance of neural functions and protection of the nervous tissue cells from oxidative stress-induced damage. Exhibits GTPase and E3 ubiquitin-protein ligase activities. Regulates dendritic spine density and synaptic neurotransmission; its ability to hydrolyze GTP is involved in the maintenance of dendritic spine density (By similarity)","subcellular_location":"Membrane; Membrane; Cytoplasm; Nucleus; Nucleus, nuclear body; Nucleus, nucleoplasm; Endosome; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle; Postsynaptic density; Perikaryon; Cell projection, neuron projection","url":"https://www.uniprot.org/uniprotkb/Q9ULX5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF112","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":[],"url":"https://opencell.sf.czbiohub.org/search/RNF112","total_profiled":1310},"omim":[{"mim_id":"601237","title":"RING FINGER PROTEIN 112; RNF112","url":"https://www.omim.org/entry/601237"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":105.5}],"url":"https://www.proteinatlas.org/search/RNF112"},"hgnc":{"alias_symbol":["BFP"],"prev_symbol":["ZNF179"]},"alphafold":{"accession":"Q9ULX5","domains":[{"cath_id":"-","chopping":"68-114","consensus_level":"high","plddt":68.1043,"start":68,"end":114},{"cath_id":"3.40.50.300","chopping":"137-197_223-365_377-406_418-427","consensus_level":"high","plddt":84.5381,"start":137,"end":427},{"cath_id":"1.20.58","chopping":"449-553","consensus_level":"high","plddt":89.7892,"start":449,"end":553}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX5-F1-predicted_aligned_error_v6.png","plddt_mean":68.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF112","jax_strain_url":"https://www.jax.org/strain/search?query=RNF112"},"sequence":{"accession":"Q9ULX5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULX5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULX5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX5"}},"corpus_meta":[{"pmid":"14993302","id":"PMC_14993302","title":"Enteropathogenic Escherichia coli (EPEC) adhesion to intestinal epithelial cells: role of bundle-forming pili (BFP), EspA filaments and intimin.","date":"2004","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/14993302","citation_count":153,"is_preprint":false},{"pmid":"10762251","id":"PMC_10762251","title":"Effects of bfp mutations on biogenesis of functional enteropathogenic Escherichia coli type IV pili.","date":"2000","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/10762251","citation_count":53,"is_preprint":false},{"pmid":"30404641","id":"PMC_30404641","title":"Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology.","date":"2018","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/30404641","citation_count":42,"is_preprint":false},{"pmid":"22819448","id":"PMC_22819448","title":"The novel phloroglucinol derivative BFP 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In the nucleotide-free (apo) state, monomeric RNF112 adopts a self-restraint conformation where the proximal end of the MD docks to a groove in the GD. At the GTP hydrolysis transition state, the MD is released and the protein forms an intertwined homodimer. Engineered RNF112 fused with C-terminal elements of ATL1 or yeast Sac1p transmembrane domains relocates to the endoplasmic reticulum and mediates membrane remodeling, demonstrating latent membrane-remodeling capacity.\",\n      \"method\": \"Crystal structure determination at different nucleotide-loading states; engineered chimeric constructs with ER-targeting domains; functional membrane remodeling assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with multiple nucleotide states plus functional chimera membrane-remodeling assay in single rigorous study\",\n      \"pmids\": [\"40198702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNF112 (Znf179) functions as a RING-domain E3 ubiquitin ligase that autoubiquitinates, regulates 26S proteasome activity by modulating 19S/20S proteasome subunit protein levels, directly interacts with TDP-43, and mediates polyubiquitination of TDP-43 both in vitro and in vivo, accelerating TDP-43 turnover and reducing insoluble TDP-43 aggregates. Knockout of Znf179 in mouse brain results in accumulation of insoluble TDP-43 and cytosolic TDP-43 inclusions in cortex, hippocampus, and midbrain.\",\n      \"method\": \"In vitro and in vivo ubiquitination assay; co-immunoprecipitation followed by mass spectrometry to identify TDP-43 as substrate; Znf179 knockout mouse model with biochemical fractionation\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of E3 ligase activity, reciprocal Co-IP/MS substrate identification, and in vivo KO model with defined molecular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"30404641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF112 directly ubiquitinates FOXM1 in gastric cancer cells, leading to decreased FOXM1 protein levels and suppressed FOXM1 transcriptional network, thereby inhibiting gastric cancer cell proliferation and invasion. The small-molecule compound RCM-1 enhances the RNF112–FOXM1 interaction and promotes FOXM1 ubiquitination.\",\n      \"method\": \"siRNA E3 ligase library screen; co-immunoprecipitation; in vitro/in vivo ubiquitination assay; RNF112 knockdown/overexpression with proliferation and invasion readouts; xenograft mouse model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — E3 ligase activity confirmed by ubiquitination assay, substrate identified by Co-IP, functional rescue in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"37288663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF112 directly interacts with the MB II domain of c-Myc through its N-terminal zinc finger motif, and its catalytic site C97 facilitates K48-linked polyubiquitination of K389 on c-Myc, targeting c-Myc for proteasomal degradation and thereby suppressing proliferation, migration, and lipid synthesis (via ACLY) in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; domain-mapping experiments; ubiquitination assay with catalytic-site (C97) mutant; K389 mutation on c-Myc; rescue with c-Myc or ACLY re-expression; in vivo xenograft model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — active-site mutagenesis (C97), substrate lysine mapping (K389), linkage specificity (K48), domain interaction mapping, and in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40178292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF112 promotes ubiquitination and degradation of NAA40 through its E3 ubiquitin ligase activity in colorectal cancer. KLF4 acts as an upstream transcriptional regulator of RNF112 by binding its promoter. Overexpression of NAA40 reverses the anti-tumor effects of RNF112 overexpression, placing RNF112 upstream of NAA40 in CRC.\",\n      \"method\": \"RNF112 overexpression/knockdown in CRC cells and xenograft; co-immunoprecipitation; ubiquitination assay; chromatin-based KLF4 promoter binding assay; NAA40 rescue experiment\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination assay with rescue, single lab, multiple but not fully orthogonal methods\",\n      \"pmids\": [\"39757327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF112 promotes ubiquitination and degradation of FOXM1 (Foxm1) in cervical cancer, reducing tumor proliferation and alleviating immunosuppression in the tumor microenvironment by protecting T lymphocytes from oxidative stress-induced mitochondrial dysfunction and ferroptosis.\",\n      \"method\": \"RNF112 knockdown (shRNA) and overexpression; xenograft mouse model; co-culture system of cancer cells with T lymphocytes; ubiquitination assay; Foxm1 inhibition rescue experiment\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assay and functional rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"42180965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Znf179 (RNF112) is acetylated on specific lysine residues; oxidative stress induces dissociation of a Znf179–HDAC1/HDAC6 complex, increasing Znf179 acetylation. Hyperacetylated Znf179 forms a transcriptional complex with Sp1 and promotes antioxidant gene expression. HDAC inhibition by SAHA further increases Znf179 acetylation and enhances this protective response.\",\n      \"method\": \"Immunoprecipitation with acetyl-lysine antibodies; co-immunoprecipitation of Znf179 with HDAC1/HDAC6; SAHA treatment; bioinformatics sequence alignment; reporter assays for antioxidant gene expression\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP for HDAC interaction, acetylation confirmed by two antibodies, functional antioxidant gene readout, single lab\",\n      \"pmids\": [\"30121389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Znf179 (RNF112) interacts with PLZF (promyelocytic leukemia zinc finger protein); the first two zinc fingers of PLZF are critical for this interaction. Co-expression of PLZF causes Znf179 to relocalize from cytoplasm to nucleus. Znf179 also increases PLZF protein abundance.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation; domain-deletion mapping; fluorescence microscopy for subcellular localization; Western blot for protein expression\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP for binding, domain mapping, and localization experiment; single lab\",\n      \"pmids\": [\"24359566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Znf179 (RNF112) is required for neuronal differentiation of P19 embryonal carcinoma cells and cerebellar granule cells. Znf179 knockdown reduces G0/G1 cell-cycle arrest, increases BrdU incorporation, and decreases levels of p35 (neuronal Cdk5 activator) and p27 (CDK inhibitor), linking Znf179 to cell cycle exit as a prerequisite for neuronal differentiation.\",\n      \"method\": \"RNA interference knockdown; flow cytometry for cell cycle analysis; BrdU incorporation assay; microarray gene expression profiling; Western blot for p35 and p27; primary cerebellar granule cell culture\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype (cell cycle exit) and molecular readouts (p35, p27), multiple orthogonal assays, single lab\",\n      \"pmids\": [\"21566658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Znf179 (RNF112) overexpression induces differentiation of primary glioblastoma multiforme cells, accompanied by elevated GFAP expression and upregulation of p53, p21, and p27, causing G0/G1 cell-cycle arrest.\",\n      \"method\": \"Znf179 overexpression in primary GBM cells; flow cytometry for cell cycle; Western blot for p53, p21, p27, GFAP; immunostaining\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — overexpression with mechanistic molecular readouts (p53/p21/p27), single lab, multiple methods\",\n      \"pmids\": [\"28684796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rnf112 knockout in mice exacerbates brain injury after intracerebral hemorrhage, associated with upregulation of TLR-4, MyD88, and phosphorylation of IKKα, IκBα, and NF-κB, indicating that Rnf112 suppresses the TLR-4/NF-κB inflammatory pathway. Conversely, Rnf112 overexpression attenuates ICH-induced brain injury by inhibiting this pathway.\",\n      \"method\": \"Rnf112 knockout mouse model with ICH induction; brain water content and neurological deficit scoring; Western blot for TLR-4/NF-κB pathway components; cytokine measurement; Rnf112 overexpression in LPS-stimulated glial cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined phenotype and molecular pathway readout, overexpression rescue, single lab\",\n      \"pmids\": [\"30454900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Purα binds directly to the Znf179 (RNF112) promoter and is required for Znf179 transcriptional induction during neuronal differentiation. Overexpression of Purα increases Znf179 expression in neuronal-differentiated P19 cells, and concurrent expression of Purα and Znf179 occurs during neuronal differentiation.\",\n      \"method\": \"DAPA (DNA affinity precipitation assay) for direct Purα–Znf179 promoter binding; Purα overexpression with Znf179 expression readout; co-expression analysis during P19 differentiation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — DAPA for direct promoter binding, functional overexpression experiment, single lab\",\n      \"pmids\": [\"33333713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BFP (brain finger protein, RNF112/ZNF179) is a novel RING finger protein predominantly expressed in the brain and induced during retinoic acid-mediated neural differentiation of P19 embryonal carcinoma cells, indicating a role in neural cell regulation.\",\n      \"method\": \"Northern blot for tissue expression; Western blot with anti-BFP antibody; retinoic acid-induced P19 differentiation model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression-level observation during differentiation with antibody detection, no direct functional mechanism established\",\n      \"pmids\": [\"9367872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mouse Bfp (RNF112) protein is detected predominantly in the nucleus, with some cytoplasmic localization, in primary neonatal brain cultures containing both neurons and glial cells, as determined by immunohistochemistry.\",\n      \"method\": \"Immunohistochemistry and in situ hybridization in mouse brain sections and primary neonatal brain cultures\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — subcellular localization established by immunohistochemistry in fixed cells, no functional consequence linked\",\n      \"pmids\": [\"9806830\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF112 (ZNF179/BFP) is a brain-enriched RING-domain E3 ubiquitin ligase and dynamin-like large GTPase whose crystal structure reveals a self-restrained monomer that dimerizes upon GTP hydrolysis and can mediate membrane remodeling when targeted to the ER; as an E3 ligase, it ubiquitinates substrates including TDP-43, FOXM1, c-Myc, and NAA40 to promote their proteasomal degradation, thereby suppressing cancer progression and neurodegeneration, while also functioning in neuronal differentiation and cell cycle exit through p27/p35/p53 pathways, and being regulated post-translationally by HDAC1/6-dependent acetylation and transcriptionally by Purα and KLF4.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF112 (ZNF179/BFP) is a brain-enriched RING-domain E3 ubiquitin ligase that drives neuronal differentiation and acts as a tumor suppressor by directing substrates to proteasomal degradation [#1, #2, #3]. Crystallographic analysis defines RNF112 as a dynamin-like large GTPase whose GTPase domain (GD) and three-helical middle domain (MD) adopt a self-restrained monomeric conformation in the apo state; at the GTP hydrolysis transition state the MD is released to form an intertwined homodimer, and ER-targeted chimeras reveal latent membrane-remodeling capacity [#0]. As an E3 ligase, RNF112 autoubiquitinates and uses its catalytic RING cysteine (C97) to assemble K48-linked polyubiquitin chains on its targets: it polyubiquitinates TDP-43 to accelerate turnover and prevent insoluble cytosolic inclusions in brain [#1], and degrades the oncogenic transcription factors FOXM1 and c-Myc as well as NAA40, thereby suppressing proliferation, invasion, and lipid synthesis across gastric, bladder, cervical, and colorectal cancers [#2, #3, #4, #5]. In neural development, RNF112 promotes cell-cycle exit required for differentiation, acting through p35/p27 in embryonal carcinoma and cerebellar granule cells and through p53/p21/p27 in glioblastoma cells [#8, #9]. RNF112 expression is transcriptionally induced by Purα and KLF4 [#11, #4], and its activity is tuned post-translationally by oxidative-stress-induced dissociation from an HDAC1/HDAC6 complex, leading to hyperacetylation and Sp1-dependent antioxidant gene expression [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established RNF112 as a brain-predominant RING finger protein whose expression is induced during neural differentiation, framing it as a candidate regulator of neural cell fate.\",\n      \"evidence\": \"Northern/Western blot tissue profiling and retinoic acid-induced P19 differentiation\",\n      \"pmids\": [\"9367872\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression correlation only, no direct functional mechanism established\", \"Did not test E3 ligase activity\", \"No substrate identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Determined RNF112 subcellular distribution as predominantly nuclear with cytoplasmic presence in brain, providing baseline localization for later functional work.\",\n      \"evidence\": \"Immunohistochemistry and in situ hybridization in mouse brain and primary neonatal cultures\",\n      \"pmids\": [\"9806830\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Static localization without functional consequence\", \"Did not resolve what governs nuclear vs cytoplasmic partitioning\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed RNF112 is required for neuronal differentiation by enforcing G0/G1 cell-cycle exit, mechanistically linking it to the p35/p27 axis.\",\n      \"evidence\": \"RNAi knockdown with cell-cycle/BrdU analysis and p35/p27 Western blot in P19 and cerebellar granule cells\",\n      \"pmids\": [\"21566658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether RNF112 acts on p35/p27 enzymatically or transcriptionally\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified PLZF as an RNF112 partner that drives its cytoplasm-to-nucleus relocalization, beginning to define RNF112's protein-interaction landscape.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, domain mapping, and fluorescence localization\",\n      \"pmids\": [\"24359566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test whether PLZF is a ubiquitination substrate\", \"Functional consequence of relocalization unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the differentiation/cell-cycle-exit role to glioblastoma via a distinct p53/p21/p27 readout, suggesting tumor-suppressive differentiation activity.\",\n      \"evidence\": \"RNF112 overexpression in primary GBM cells with cell-cycle and p53/p21/p27/GFAP analysis\",\n      \"pmids\": [\"28684796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect cell-cycle effects to direct ubiquitination targets\", \"Overexpression only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined RNF112 as a bona fide E3 ligase that ubiquitinates TDP-43 to suppress aggregation in vivo, establishing its mechanistic role in proteostasis and neurodegeneration.\",\n      \"evidence\": \"In vitro/in vivo ubiquitination assays, Co-IP/MS substrate identification, and Znf179 knockout mouse with biochemical fractionation\",\n      \"pmids\": [\"30404641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the ubiquitinated lysines on TDP-43\", \"Relationship between proteasome modulation and direct substrate ubiquitination not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed post-translational control of RNF112 by oxidative-stress-regulated acetylation, coupling redox state to an antioxidant transcriptional response via Sp1.\",\n      \"evidence\": \"Acetyl-lysine IP, reciprocal Co-IP with HDAC1/HDAC6, SAHA treatment, and antioxidant reporter assays\",\n      \"pmids\": [\"30121389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not link acetylation state to E3 ligase activity\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed RNF112 suppresses TLR-4/NF-\\u03baB inflammatory signaling in brain injury, broadening its protective role beyond proteostasis.\",\n      \"evidence\": \"Rnf112 knockout mouse intracerebral hemorrhage model with NF-\\u03baB pathway Western blots and overexpression rescue\",\n      \"pmids\": [\"30454900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between RNF112 and TLR-4/NF-\\u03baB components not defined (no direct substrate)\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified Pur\\u03b1 as a direct transcriptional activator of RNF112 during neuronal differentiation, defining an upstream input to its expression.\",\n      \"evidence\": \"DNA affinity precipitation assay for promoter binding and Pur\\u03b1 overexpression in differentiating P19 cells\",\n      \"pmids\": [\"33333713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish chromatin occupancy in vivo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated RNF112 directly ubiquitinates FOXM1 to inhibit gastric cancer proliferation/invasion, establishing it as a druggable tumor suppressor (via RCM-1).\",\n      \"evidence\": \"siRNA E3 ligase screen, Co-IP, in vitro/in vivo ubiquitination, and xenograft model\",\n      \"pmids\": [\"37288663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map ubiquitinated FOXM1 lysines or linkage type\", \"RCM-1 mechanism of interaction enhancement not structurally resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided high-resolution mechanism for c-Myc degradation, mapping the N-terminal zinc finger interaction with MB II, catalytic C97, and K48-linked ubiquitination of K389.\",\n      \"evidence\": \"Co-IP, domain/active-site (C97) and substrate-lysine (K389) mutagenesis, linkage analysis, and xenograft rescue in bladder cancer\",\n      \"pmids\": [\"40178292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether the same residues mediate other substrate interactions\", \"Did not connect to the GTPase activity\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structural basis of RNF112 as a self-restrained dynamin-like GTPase that dimerizes upon hydrolysis and has latent membrane-remodeling capacity.\",\n      \"evidence\": \"Crystal structures at multiple nucleotide states plus ER-targeted chimera membrane-remodeling assays\",\n      \"pmids\": [\"40198702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native membrane substrate/physiological membrane target unknown\", \"Relationship between GTPase cycle and E3 ligase activity unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed RNF112 in a KLF4\\u2192RNF112\\u22a3NAA40 axis in colorectal cancer, identifying both an upstream activator and a new degradation substrate.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, KLF4 promoter-binding assay, and NAA40 rescue in CRC cells and xenografts\",\n      \"pmids\": [\"39757327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NAA40 ubiquitination lysines and linkage not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended FOXM1 degradation to cervical cancer with an immunological consequence, linking RNF112 to protection of T lymphocytes from ferroptosis in the tumor microenvironment.\",\n      \"evidence\": \"shRNA/overexpression, xenograft, cancer-T cell co-culture, ubiquitination assay, and Foxm1 inhibition rescue\",\n      \"pmids\": [\"42180965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect on T-cell ferroptosis not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dynamin-like GTPase cycle and membrane-remodeling capacity integrate with the E3 ligase activity, and whether they operate in the same physiological pathway, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological membrane substrate identified\", \"Coupling between nucleotide-dependent dimerization and substrate ubiquitination unknown\", \"Unified model linking neuronal, tumor-suppressive, and membrane functions absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TDP-43\", \"FOXM1\", \"MYC\", \"NAA40\", \"PLZF\", \"HDAC1\", \"HDAC6\", \"Sp1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}