{"gene":"RNF144A","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2014,"finding":"RNF144A is an RBR-domain E3 ubiquitin ligase that ubiquitinates DNA-PKcs in vitro and in vivo, promoting its proteasomal degradation and thereby sensitizing cells to DNA damage-induced apoptosis. RNF144A expression is induced by DNA damage in a p53-dependent manner. RNF144A localizes to cytoplasmic vesicles and the plasma membrane, where it interacts with cytoplasmic DNA-PKcs.","method":"In vitro ubiquitination assay, co-immunoprecipitation, subcellular fractionation, siRNA knockdown with cell viability/apoptosis readouts, p53-dependent expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay plus in vivo co-IP, knockdown phenotype with rescue by DNA-PK inhibitor, multiple orthogonal methods in a single focused study","pmids":["24979766"],"is_preprint":false},{"year":2015,"finding":"The transmembrane (TM) domain of RNF144A has two independent functions: membrane localization and activation of E3 ligase activity. Self-association mediated through a GXXXG motif (G252XXXG256) in the TM domain is required for full ubiquitin ligase activity. Deletion of the TM domain abolishes membrane localization and significantly reduces E3 activity. A G252L/G256L mutant retains membrane localization but is defective in self-association and E3 activity. Loss of membrane localization alone does not abolish E3 activity if self-association is preserved, but additional G252L/G256L mutations block activity. A cancer-associated G252D mutant retains self-association and ligase activity but loses membrane localization and is rapidly turned over.","method":"Deletion and point mutagenesis of TM/GXXXG domains, in vitro ubiquitination assays, membrane fractionation, co-immunoprecipitation for self-association","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution-level in vitro ubiquitination combined with mutagenesis and multiple orthogonal assays (fractionation, co-IP) in a single rigorous study","pmids":["26216882"],"is_preprint":false},{"year":2017,"finding":"RNF144A interacts with PARP1 through its carboxy-terminal region containing the transmembrane domain, and targets PARP1 for K48-linked ubiquitination and subsequent proteasomal degradation. RNF144A-induced reduction of PARP1 renders breast cancer cells resistant to the PARP inhibitor olaparib; conversely, RNF144A knockdown increases PARP1 levels and sensitizes cells to olaparib.","method":"Co-immunoprecipitation, ubiquitination assays, RNF144A overexpression/knockdown with PARP1 protein-level readouts, olaparib sensitivity assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal co-IP and in-cell ubiquitination assays with functional (drug sensitivity) phenotype, single lab, multiple complementary methods","pmids":["29212245"],"is_preprint":false},{"year":2018,"finding":"RNF144A promotes EGFR ubiquitination, maintains EGFR protein stability, and prolongs EGF/EGFR signaling during EGF stimulation. EGFR ligands (but not DNA-damaging agents) induce a DNA-PKcs-independent interaction between RNF144A and EGFR. Depletion of RNF144A decreases EGFR expression and EGF/EGFR signaling, impairs G1/S progression gene activation, and reduces EGF-dependent cell proliferation. RNF144A also regulates EGFR transport in intracellular vesicles during EGF treatment.","method":"RNF144A knockdown/knockout with EGFR protein-level and signaling readouts, co-immunoprecipitation, cell proliferation assays, G1/S gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple independent knockdown approaches plus KO with defined molecular and cellular phenotypes, single lab","pmids":["30171075"],"is_preprint":false},{"year":2018,"finding":"RNF144A promoter contains a CpG island that is hypermethylated in breast cancer, leading to transcriptional silencing. The methyl-CpG-binding domain protein MBD4 contributes to this silencing, as genetic knockdown or pharmacological inhibition of MBD4 increases RNF144A expression. Treatment with the DNA methylation inhibitor 5-Aza-2-deoxycytidine reactivates RNF144A expression in hypermethylated cells.","method":"Bisulfite sequencing/methylation analysis, 5-Aza-2-deoxycytidine treatment, MBD4 siRNA knockdown and inhibitor treatment with RNF144A expression readouts","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct methylation mapping with pharmacological and genetic interventions, single lab, multiple orthogonal methods","pmids":["29473320"],"is_preprint":false},{"year":2019,"finding":"RNF144A interacts with HSPA2 and targets it for ubiquitination and proteasomal degradation. Ligase activity-defective RNF144A mutants fail to induce HSPA2 ubiquitination/degradation and fail to suppress breast cancer cell proliferation, migration, and invasion. Ectopic HSPA2 expression rescues the anti-tumor effects of RNF144A overexpression.","method":"Quantitative proteomics, co-immunoprecipitation, ubiquitination assays, ligase-dead mutagenesis, HSPA2 rescue experiments, in vitro and in vivo tumor assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS-based substrate identification, co-IP, in-cell ubiquitination, mutagenesis of catalytic residues, and epistatic rescue experiments in multiple complementary assays","pmids":["31406303"],"is_preprint":false},{"year":2020,"finding":"The solution NMR structure of the RNF144A RING finger domain was determined. The domain binds two zinc atoms (confirmed by spectrophotometric metallochromic indicator assay) and the structure delineates the active site and E2-binding interface at atomic resolution.","method":"Solution NMR structure determination, metallochromic indicator assay for zinc stoichiometry","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation of zinc stoichiometry, single lab but direct structural determination","pmids":["32557973"],"is_preprint":false},{"year":2020,"finding":"Under oxidative stress, VRK3 translocates from nucleus to cytoplasm, enabling its interaction with RNF144A, which promotes VRK3 polyubiquitylation and proteasomal degradation. Loss of VRK3 derepresses ERK activity, leading to ERK-dependent apoptosis. RNF144A overexpression increases ERK activity and promotes apoptosis via VRK3 downregulation; RNF144A depletion stabilizes VRK3 and protects cells from excessive ERK activation.","method":"Co-immunoprecipitation, ubiquitination assays, RNF144A overexpression/knockdown with VRK3 protein-level and ERK activity readouts, subcellular fractionation under oxidative stress","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in-cell ubiquitination, fractionation, and functional ERK/apoptosis readouts, single lab, multiple complementary methods","pmids":["33067254"],"is_preprint":false},{"year":2021,"finding":"RNF144A interacts with PD-L1 at the plasma membrane and intracellular vesicles and promotes its poly-ubiquitination and proteasomal degradation. RNF144A knockout in mice stabilizes PD-L1 and reduces tumor-infiltrating CD8+ T cell populations in carcinogen-induced bladder tumors. RNF144A also targets BMI1 for degradation.","method":"Co-immunoprecipitation, ubiquitination assays, Rnf144a knockout mouse model with carcinogen (BBN) challenge, immunohistochemistry and flow cytometry for CD8+ T cells","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model combined with co-IP, ubiquitination assays, and functional immune readout; replicates and extends prior findings about DNA-PKcs targeting","pmids":["34400221"],"is_preprint":false},{"year":2021,"finding":"RNF144A interacts with LIN28B via co-immunoprecipitation and promotes its ubiquitination and proteasomal degradation in ovarian cancer cells. Ectopic LIN28B expression restores stem cell pluripotency-associated transcription factors in RNF144A-overexpressing cells, establishing an RNF144A–LIN28B epistatic relationship.","method":"Co-immunoprecipitation, ubiquitination assays, RNF144A overexpression/knockdown with LIN28B protein-level and stem-cell marker readouts, LIN28B rescue experiment, mouse xenograft model","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, in-cell ubiquitination, epistatic rescue, and in vivo xenograft, single lab","pmids":["33978933"],"is_preprint":false},{"year":2022,"finding":"RNF144A interacts with transcription factor YY1 and promotes its ubiquitination-dependent proteasomal degradation, thereby blocking YY1-driven transcriptional activation of GMFG. Ectopic GMFG expression partially rescues the anti-proliferative, anti-migratory, and anti-invasive effects of RNF144A overexpression in breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays, transcriptome profiling (Affymetrix array), quantitative RT-PCR and western blot for GMFG, GMFG rescue experiment","journal":"Medical oncology (Northwood, London, England)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, ubiquitination, transcriptomic identification, and epistatic rescue, single lab","pmids":["35103856"],"is_preprint":false},{"year":2023,"finding":"RNF144A interacts with STING and promotes K6-linked ubiquitination of STING at lysine K236, enhancing STING translocation from the ER to the Golgi and downstream innate immune signaling. The K236R STING mutant shows reduced activity in innate immune signaling. RNF144A does not affect RNA virus- or cytosolic RNA-triggered innate immune responses (negative finding for RNA sensing). Rnf144a-deficient cells and mice show impaired DNA virus-triggered signaling.","method":"Co-immunoprecipitation, ubiquitination assays with linkage-specific antibodies, K236R STING mutant analysis, RNF144A knockdown/overexpression with interferon signaling readouts, Rnf144a-deficient mouse model with DNA virus challenge","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical ubiquitination assay with site-specific mutagenesis, in vivo KO mouse model, and multiple orthogonal functional readouts","pmids":["37955227"],"is_preprint":false},{"year":2023,"finding":"In hepatocellular carcinoma cells, RNF144A mediates ubiquitination of DNA-PKcs following combined radiation and topoisomerase I inhibitor treatment, reducing DNA-PKcs prosurvival signaling. In PLC5 cells, RNF144A undergoes nuclear translocation and is decreased, correlating with DNA-PKcs accumulation and radioresistance. The ubiquitin/proteasome system is required for this effect (reversed by proteasome inhibition).","method":"Western blotting, immunoprecipitation, subcellular fractionation, confocal microscopy, proteasome inhibitor treatment","journal":"Journal of clinical and translational hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — immunoprecipitation and fractionation in cell lines, single lab, limited mechanistic follow-up; extends prior DNA-PKcs finding to hepatocellular carcinoma context","pmids":["36969901"],"is_preprint":false},{"year":2024,"finding":"RNF144A interacts with BECN1 (Beclin-1) and promotes its K48-linked ubiquitination at K117 and K427, leading to proteasomal degradation of BECN1 and reduced autophagosome accumulation. This inhibits autophagy during L. monocytogenes infection. These two ubiquitination sites on BECN1 are required for the functional effect on autophagy and bacterial infection. rnf144a-deficient mice are protected from Lm infection and show enhanced innate immune responses.","method":"Co-immunoprecipitation, ubiquitination assays with K48-linkage-specific antibodies, site-directed mutagenesis of BECN1 ubiquitination sites (K117R, K427R), autophagosome flux assays, rnf144a KO mouse model with L. monocytogenes infection, proximity ligation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in-cell ubiquitination with linkage-specific antibodies, site-specific mutagenesis of substrate, in vivo KO mouse infection model, multiple orthogonal methods","pmids":["39608349"],"is_preprint":false},{"year":2024,"finding":"FOXF2 transcriptionally activates RNF144A expression, and the resulting RNF144A protein promotes ubiquitination and proteasomal degradation of FTO (an m6A demethylase). This axis contributes to suppression of M2 macrophage (TAM) polarization in esophageal squamous cell carcinoma.","method":"Overexpression/knockdown of FOXF2 and RNF144A with FTO protein-level readouts, ubiquitination assays, macrophage polarization assays, promoter transcription analysis","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in-cell ubiquitination and functional rescue assays, single lab, identifies FTO as a new substrate","pmids":["39447407"],"is_preprint":false},{"year":2025,"finding":"RNF144A promotes proteasomal degradation of VRK2, which reduces VRK2-mediated phosphorylation of G3BP1, thereby promoting stress granule (SG) assembly. Overexpression of VRK2 inhibits SG formation and sensitizes cells to stress and chemotherapy. This establishes an RNF144A–VRK2–G3BP1 axis regulating SG formation.","method":"VRK2 overexpression/knockdown, RNF144A overexpression with VRK2 protein-level readouts, G3BP1 phosphorylation assays, stress granule imaging, cell viability under chemotherapy","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in-cell degradation assays, phosphorylation readout, SG imaging with functional chemotherapy sensitivity, single lab","pmids":["40204710"],"is_preprint":false},{"year":2025,"finding":"RNF144A interacts with thyroid-stimulating hormone receptor (TSHR) and promotes its ubiquitination and destabilization in lung fibroblasts. MSC-derived exosomes increase RNF144A expression, which suppresses TSHR protein levels and protects against LPS-induced pneumonia in vitro and in vivo. Re-expression of TSHR reverses the protective effects of MSC exosomes.","method":"GST pull-down, co-immunoprecipitation, immunoprecipitation, RNF144A knockdown with TSHR protein-level readouts, LPS pneumonia mouse model","journal":"Applied biochemistry and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — GST pull-down plus co-IP plus in vivo model, single lab, identifies TSHR as a new substrate","pmids":["41123861"],"is_preprint":false}],"current_model":"RNF144A is a single-pass transmembrane RBR (RING1-IBR-RING2) E3 ubiquitin ligase that localizes to cytoplasmic vesicles and the plasma membrane via its TM domain; its ligase activity requires both membrane localization and TM domain-mediated self-association through a GXXXG motif. It is transcriptionally induced by p53 following DNA damage and can be epigenetically silenced by promoter hypermethylation via MBD4. RNF144A ubiquitinates and promotes proteasomal degradation of multiple substrates including DNA-PKcs (K48-linked, apoptosis during DNA damage), PARP1, HSPA2, PD-L1, BMI1, LIN28B, YY1, VRK3, VRK2, BECN1 (K48-linked at K117/K427, suppressing autophagy), FTO, and TSHR; it also promotes K6-linked ubiquitination of STING at K236 to enhance its ER-to-Golgi translocation and antiviral innate immune signaling. Through regulated substrate degradation, RNF144A controls DNA repair signaling, EGF/EGFR pathway activity, ERK-dependent apoptosis, stress granule assembly, autophagy, and innate immune responses."},"narrative":{"mechanistic_narrative":"RNF144A is a membrane-anchored RBR (RING1-IBR-RING2) E3 ubiquitin ligase that controls diverse cellular programs by directing substrates to proteasomal degradation, including DNA repair signaling, growth-factor signaling, apoptosis, autophagy, and innate immunity [PMID:24979766, PMID:34400221, PMID:37955227, PMID:39608349]. Its catalytic RING module coordinates two zinc atoms and presents the active site and E2-binding interface [PMID:32557973], while a C-terminal transmembrane (TM) domain performs two distinct functions: it targets RNF144A to cytoplasmic vesicles and the plasma membrane and, through self-association via a GXXXG (G252XXXG256) motif, activates ligase activity—mutation of these glycines preserves membrane localization but abolishes both self-association and catalysis [PMID:24979766, PMID:26216882]. RNF144A is transcriptionally induced by p53 after DNA damage and can be epigenetically silenced by promoter CpG hypermethylation acting through MBD4 [PMID:24979766, PMID:29473320]. Through K48-linked ubiquitination it degrades DNA-PKcs to sensitize cells to DNA damage-induced apoptosis [PMID:24979766, PMID:36969901] and degrades BECN1 at K117/K427 to suppress autophagy during bacterial infection [PMID:39608349]; it likewise drives degradation of PARP1, HSPA2, PD-L1, BMI1, LIN28B, YY1, VRK3, VRK2, FTO, and TSHR, coupling its ligase output to PARP-inhibitor sensitivity, tumor-immune surveillance, ERK-dependent apoptosis, and stress granule assembly [PMID:29212245, PMID:31406303, PMID:33067254, PMID:34400221, PMID:33978933, PMID:35103856, PMID:40204710]. In contrast to its degradative activity, RNF144A promotes non-degradative K6-linked ubiquitination of STING at K236 to enhance ER-to-Golgi translocation and DNA virus-triggered antiviral signaling [PMID:37955227]. RNF144A also stabilizes EGFR and prolongs EGF/EGFR signaling during ligand stimulation, indicating that its ubiquitination outputs are substrate- and stimulus-dependent rather than uniformly destabilizing [PMID:30171075].","teleology":[{"year":2014,"claim":"Established RNF144A as a functional RBR E3 ligase with a defined substrate and biological role, answering whether this protein has catalytic ubiquitination activity and what it does.","evidence":"In vitro ubiquitination, co-IP, subcellular fractionation, and p53-dependent expression analysis showing RNF144A degrades DNA-PKcs and sensitizes to DNA damage apoptosis","pmids":["24979766"],"confidence":"High","gaps":["Ubiquitin linkage type on DNA-PKcs not fully resolved at this stage","Mechanism of vesicle/plasma membrane targeting not yet defined"]},{"year":2015,"claim":"Resolved how the TM domain governs activity, showing that membrane targeting and GXXXG-mediated self-association are separable and that self-association is required for full ligase activity.","evidence":"TM/GXXXG deletion and point mutagenesis (G252L/G256L, G252D) with in vitro ubiquitination, membrane fractionation, and co-IP for self-association","pmids":["26216882"],"confidence":"High","gaps":["Structural basis of TM self-association not determined","How self-association allosterically activates the catalytic RBR module is unknown"]},{"year":2017,"claim":"Extended the substrate repertoire to PARP1 and linked RNF144A levels to chemotherapy response, addressing how RNF144A modulates PARP-inhibitor sensitivity.","evidence":"Reciprocal co-IP, K48-linked in-cell ubiquitination assays, and olaparib sensitivity assays in breast cancer cells","pmids":["29212245"],"confidence":"Medium","gaps":["Single lab, no in vivo confirmation","Direct ubiquitination site on PARP1 not mapped"]},{"year":2018,"claim":"Showed RNF144A is not uniformly degradative, revealing a stimulus-dependent role in stabilizing EGFR and prolonging EGF/EGFR signaling.","evidence":"Knockdown/knockout with EGFR protein-level and signaling readouts, co-IP, proliferation and G1/S gene expression assays","pmids":["30171075"],"confidence":"Medium","gaps":["Ubiquitin linkage type stabilizing EGFR not defined","How the same ligase stabilizes some substrates while degrading others mechanistically unresolved"]},{"year":2018,"claim":"Identified an epigenetic mechanism silencing RNF144A in cancer, answering how its expression is lost in tumors.","evidence":"Bisulfite methylation analysis, 5-Aza-2-deoxycytidine reactivation, and MBD4 knockdown/inhibition with RNF144A expression readouts","pmids":["29473320"],"confidence":"Medium","gaps":["Direct MBD4 binding to the RNF144A promoter not demonstrated","Single lab"]},{"year":2019,"claim":"Used unbiased proteomics to identify HSPA2 as a substrate and tied catalytic activity to tumor suppression via rescue epistasis.","evidence":"Quantitative proteomics, ligase-dead mutagenesis, in-cell ubiquitination, and HSPA2 rescue with in vitro and in vivo tumor assays","pmids":["31406303"],"confidence":"High","gaps":["HSPA2 ubiquitination sites not mapped","Linkage type not specified"]},{"year":2020,"claim":"Provided atomic-resolution detail of the catalytic RING domain, defining zinc coordination and the E2-binding interface.","evidence":"Solution NMR structure of the RING finger domain and metallochromic zinc stoichiometry assay","pmids":["32557973"],"confidence":"High","gaps":["Full-length or IBR/RING2 structure not determined","No structure of substrate- or E2-bound complex"]},{"year":2020,"claim":"Connected RNF144A to ERK-dependent apoptosis through stress-regulated degradation of VRK3.","evidence":"Co-IP, in-cell ubiquitination, oxidative-stress fractionation, and RNF144A perturbation with VRK3/ERK and apoptosis readouts","pmids":["33067254"],"confidence":"Medium","gaps":["Single lab","VRK3 ubiquitination sites and linkage not mapped"]},{"year":2021,"claim":"Established an in vivo immunoregulatory role, showing RNF144A degrades PD-L1 (and BMI1) and shapes tumor-infiltrating CD8+ T cells.","evidence":"Co-IP, ubiquitination assays, and Rnf144a knockout mice challenged with carcinogen (BBN) with IHC/flow cytometry for CD8+ T cells","pmids":["34400221"],"confidence":"High","gaps":["BMI1 mechanism less developed than PD-L1","PD-L1 ubiquitination sites not mapped"]},{"year":2021,"claim":"Added LIN28B as a substrate linking RNF144A to stem-cell pluripotency programs in ovarian cancer.","evidence":"Co-IP, ubiquitination assays, LIN28B rescue of pluripotency markers, and xenograft model","pmids":["33978933"],"confidence":"Medium","gaps":["Single lab","Direct versus indirect ubiquitination of LIN28B not fully distinguished"]},{"year":2022,"claim":"Showed RNF144A controls transcription indirectly by degrading the factor YY1 and blocking GMFG activation.","evidence":"Co-IP, ubiquitination, transcriptome profiling, and GMFG rescue in breast cancer cells","pmids":["35103856"],"confidence":"Medium","gaps":["YY1 ubiquitination site not mapped","Single lab"]},{"year":2023,"claim":"Revealed a non-degradative ubiquitination output, with K6-linked ubiquitination of STING at K236 promoting ER-to-Golgi translocation and DNA-virus antiviral signaling.","evidence":"Linkage-specific ubiquitination assays, K236R mutant analysis, and Rnf144a-deficient mice with DNA virus challenge; negative result for RNA sensing","pmids":["37955227"],"confidence":"High","gaps":["Structural basis for K6 versus K48 linkage selection unknown","How membrane-localized RNF144A engages STING at the ER not detailed"]},{"year":2023,"claim":"Extended DNA-PKcs targeting to hepatocellular carcinoma and linked RNF144A nuclear translocation/loss to radioresistance.","evidence":"Western blotting, IP, fractionation, confocal microscopy, and proteasome inhibitor treatment in HCC cells after radiation/topoisomerase inhibitor","pmids":["36969901"],"confidence":"Medium","gaps":["Mechanism and signal driving nuclear translocation unresolved","Limited mechanistic follow-up, single lab"]},{"year":2024,"claim":"Defined RNF144A as a suppressor of autophagy through site-specific K48 ubiquitination of BECN1 at K117/K427, with an in vivo anti-bacterial consequence.","evidence":"Linkage-specific ubiquitination, BECN1 K117R/K427R mutagenesis, autophagosome flux, PLA, and rnf144a KO mice infected with L. monocytogenes","pmids":["39608349"],"confidence":"High","gaps":["How autophagy suppression integrates with STING-driven antiviral role not reconciled","E2 partner for BECN1 ubiquitination not identified"]},{"year":2024,"claim":"Placed RNF144A within a FOXF2-driven transcriptional axis that degrades the m6A demethylase FTO to suppress M2 macrophage polarization.","evidence":"FOXF2/RNF144A perturbation with FTO readouts, ubiquitination assays, macrophage polarization, and promoter transcription analysis","pmids":["39447407"],"confidence":"Medium","gaps":["FTO ubiquitination sites not mapped","Single lab"]},{"year":2025,"claim":"Identified an RNF144A-VRK2-G3BP1 axis regulating stress granule assembly and chemotherapy sensitivity.","evidence":"RNF144A-driven VRK2 degradation, G3BP1 phosphorylation readouts, stress granule imaging, and viability assays under chemotherapy","pmids":["40204710"],"confidence":"Medium","gaps":["Direct ubiquitination of VRK2 by RNF144A versus indirect effect not fully resolved","Single lab"]},{"year":2025,"claim":"Added TSHR as a substrate in lung fibroblasts and connected MSC-exosome-induced RNF144A to protection from LPS pneumonia.","evidence":"GST pull-down, co-IP, knockdown with TSHR readouts, and LPS pneumonia mouse model with TSHR rescue","pmids":["41123861"],"confidence":"Medium","gaps":["TSHR ubiquitination sites and linkage not mapped","Single lab"]},{"year":null,"claim":"It remains unknown what determines RNF144A linkage-type selection (K48 degradative versus K6 non-degradative) and substrate choice across its many reported targets, and how its membrane localization is reconciled with action on nuclear, cytosolic, and ER-resident substrates.","evidence":"No timeline study systematically defines the structural/regulatory determinants of linkage specificity or substrate selection","pmids":[],"confidence":"Low","gaps":["No unifying mechanism for linkage choice","Cofactors/adaptors governing substrate selection unidentified","Relationship between subcellular targeting and substrate access unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,5,11,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,8,11,13]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,8,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,11,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["DNA-PKCS (PRKDC)","EGFR","PARP1","HSPA2","PD-L1 (CD274)","STING (TMEM173)","BECN1","VRK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50876","full_name":"E3 ubiquitin-protein ligase RNF144A","aliases":["RING finger protein 144A","UbcM4-interacting protein 4","Ubiquitin-conjugating enzyme 7-interacting protein 4"],"length_aa":292,"mass_kda":32.9,"function":"E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:26216882). Mediates the ubiquitination and degradation of the DNA damage kinase PRKDC during DNA damage (PubMed:24979766). Positively regulates DNA virus or exogenous cytosolic DNA-triggered innate immune response by mediating STING1 ubiquitination and increasing its 'Lys-6'-linked ubiquitination and translocation from the endoplasmic reticulum to the Golgi leading to downstream signaling pathways (PubMed:37955227). Plays a positive role in EGF-dependent cell proliferation by prolonging EGF/EGFR signaling during EGF stimulation through EGFR ubiquitination (PubMed:30171075). Increases ERK activity independently of EGFR signaling by promoting polyubiquitination and subsequent degradation of VRK3 in the cytosol (PubMed:33067254)","subcellular_location":"Cell membrane; Cytoplasmic vesicle membrane; Endosome membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P50876/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF144A","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/RNF144A","total_profiled":1310},"omim":[{"mim_id":"619454","title":"RING FINGER PROTEIN 144A; RNF144A","url":"https://www.omim.org/entry/619454"},{"mim_id":"618869","title":"RING FINGER PROTEIN 144B; RNF144B","url":"https://www.omim.org/entry/618869"},{"mim_id":"131550","title":"EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR","url":"https://www.omim.org/entry/131550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":54.5}],"url":"https://www.proteinatlas.org/search/RNF144A"},"hgnc":{"alias_symbol":["UBCE7IP4","KIAA0161","hUIP4"],"prev_symbol":["RNF144"]},"alphafold":{"accession":"P50876","domains":[{"cath_id":"3.30.40.10","chopping":"18-102","consensus_level":"high","plddt":91.5618,"start":18,"end":102},{"cath_id":"-","chopping":"106-144","consensus_level":"high","plddt":84.9569,"start":106,"end":144},{"cath_id":"-","chopping":"180-238","consensus_level":"medium","plddt":86.9095,"start":180,"end":238},{"cath_id":"1.20.5","chopping":"240-269","consensus_level":"medium","plddt":91.0617,"start":240,"end":269}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50876","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50876-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50876-F1-predicted_aligned_error_v6.png","plddt_mean":81.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF144A","jax_strain_url":"https://www.jax.org/strain/search?query=RNF144A"},"sequence":{"accession":"P50876","fasta_url":"https://rest.uniprot.org/uniprotkb/P50876.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50876/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50876"}},"corpus_meta":[{"pmid":"8724849","id":"PMC_8724849","title":"Prediction of the coding sequences of unidentified human genes. V. 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RNF144A expression is induced by DNA damage in a p53-dependent manner. RNF144A localizes to cytoplasmic vesicles and the plasma membrane, where it interacts with cytoplasmic DNA-PKcs.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, subcellular fractionation, siRNA knockdown with cell viability/apoptosis readouts, p53-dependent expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay plus in vivo co-IP, knockdown phenotype with rescue by DNA-PK inhibitor, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"24979766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The transmembrane (TM) domain of RNF144A has two independent functions: membrane localization and activation of E3 ligase activity. Self-association mediated through a GXXXG motif (G252XXXG256) in the TM domain is required for full ubiquitin ligase activity. Deletion of the TM domain abolishes membrane localization and significantly reduces E3 activity. A G252L/G256L mutant retains membrane localization but is defective in self-association and E3 activity. Loss of membrane localization alone does not abolish E3 activity if self-association is preserved, but additional G252L/G256L mutations block activity. A cancer-associated G252D mutant retains self-association and ligase activity but loses membrane localization and is rapidly turned over.\",\n      \"method\": \"Deletion and point mutagenesis of TM/GXXXG domains, in vitro ubiquitination assays, membrane fractionation, co-immunoprecipitation for self-association\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution-level in vitro ubiquitination combined with mutagenesis and multiple orthogonal assays (fractionation, co-IP) in a single rigorous study\",\n      \"pmids\": [\"26216882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNF144A interacts with PARP1 through its carboxy-terminal region containing the transmembrane domain, and targets PARP1 for K48-linked ubiquitination and subsequent proteasomal degradation. RNF144A-induced reduction of PARP1 renders breast cancer cells resistant to the PARP inhibitor olaparib; conversely, RNF144A knockdown increases PARP1 levels and sensitizes cells to olaparib.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, RNF144A overexpression/knockdown with PARP1 protein-level readouts, olaparib sensitivity assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal co-IP and in-cell ubiquitination assays with functional (drug sensitivity) phenotype, single lab, multiple complementary methods\",\n      \"pmids\": [\"29212245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNF144A promotes EGFR ubiquitination, maintains EGFR protein stability, and prolongs EGF/EGFR signaling during EGF stimulation. EGFR ligands (but not DNA-damaging agents) induce a DNA-PKcs-independent interaction between RNF144A and EGFR. Depletion of RNF144A decreases EGFR expression and EGF/EGFR signaling, impairs G1/S progression gene activation, and reduces EGF-dependent cell proliferation. RNF144A also regulates EGFR transport in intracellular vesicles during EGF treatment.\",\n      \"method\": \"RNF144A knockdown/knockout with EGFR protein-level and signaling readouts, co-immunoprecipitation, cell proliferation assays, G1/S gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple independent knockdown approaches plus KO with defined molecular and cellular phenotypes, single lab\",\n      \"pmids\": [\"30171075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNF144A promoter contains a CpG island that is hypermethylated in breast cancer, leading to transcriptional silencing. The methyl-CpG-binding domain protein MBD4 contributes to this silencing, as genetic knockdown or pharmacological inhibition of MBD4 increases RNF144A expression. Treatment with the DNA methylation inhibitor 5-Aza-2-deoxycytidine reactivates RNF144A expression in hypermethylated cells.\",\n      \"method\": \"Bisulfite sequencing/methylation analysis, 5-Aza-2-deoxycytidine treatment, MBD4 siRNA knockdown and inhibitor treatment with RNF144A expression readouts\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct methylation mapping with pharmacological and genetic interventions, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29473320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RNF144A interacts with HSPA2 and targets it for ubiquitination and proteasomal degradation. Ligase activity-defective RNF144A mutants fail to induce HSPA2 ubiquitination/degradation and fail to suppress breast cancer cell proliferation, migration, and invasion. Ectopic HSPA2 expression rescues the anti-tumor effects of RNF144A overexpression.\",\n      \"method\": \"Quantitative proteomics, co-immunoprecipitation, ubiquitination assays, ligase-dead mutagenesis, HSPA2 rescue experiments, in vitro and in vivo tumor assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS-based substrate identification, co-IP, in-cell ubiquitination, mutagenesis of catalytic residues, and epistatic rescue experiments in multiple complementary assays\",\n      \"pmids\": [\"31406303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The solution NMR structure of the RNF144A RING finger domain was determined. The domain binds two zinc atoms (confirmed by spectrophotometric metallochromic indicator assay) and the structure delineates the active site and E2-binding interface at atomic resolution.\",\n      \"method\": \"Solution NMR structure determination, metallochromic indicator assay for zinc stoichiometry\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation of zinc stoichiometry, single lab but direct structural determination\",\n      \"pmids\": [\"32557973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Under oxidative stress, VRK3 translocates from nucleus to cytoplasm, enabling its interaction with RNF144A, which promotes VRK3 polyubiquitylation and proteasomal degradation. Loss of VRK3 derepresses ERK activity, leading to ERK-dependent apoptosis. RNF144A overexpression increases ERK activity and promotes apoptosis via VRK3 downregulation; RNF144A depletion stabilizes VRK3 and protects cells from excessive ERK activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, RNF144A overexpression/knockdown with VRK3 protein-level and ERK activity readouts, subcellular fractionation under oxidative stress\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in-cell ubiquitination, fractionation, and functional ERK/apoptosis readouts, single lab, multiple complementary methods\",\n      \"pmids\": [\"33067254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF144A interacts with PD-L1 at the plasma membrane and intracellular vesicles and promotes its poly-ubiquitination and proteasomal degradation. RNF144A knockout in mice stabilizes PD-L1 and reduces tumor-infiltrating CD8+ T cell populations in carcinogen-induced bladder tumors. RNF144A also targets BMI1 for degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Rnf144a knockout mouse model with carcinogen (BBN) challenge, immunohistochemistry and flow cytometry for CD8+ T cells\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model combined with co-IP, ubiquitination assays, and functional immune readout; replicates and extends prior findings about DNA-PKcs targeting\",\n      \"pmids\": [\"34400221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF144A interacts with LIN28B via co-immunoprecipitation and promotes its ubiquitination and proteasomal degradation in ovarian cancer cells. Ectopic LIN28B expression restores stem cell pluripotency-associated transcription factors in RNF144A-overexpressing cells, establishing an RNF144A–LIN28B epistatic relationship.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, RNF144A overexpression/knockdown with LIN28B protein-level and stem-cell marker readouts, LIN28B rescue experiment, mouse xenograft model\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, in-cell ubiquitination, epistatic rescue, and in vivo xenograft, single lab\",\n      \"pmids\": [\"33978933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF144A interacts with transcription factor YY1 and promotes its ubiquitination-dependent proteasomal degradation, thereby blocking YY1-driven transcriptional activation of GMFG. Ectopic GMFG expression partially rescues the anti-proliferative, anti-migratory, and anti-invasive effects of RNF144A overexpression in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, transcriptome profiling (Affymetrix array), quantitative RT-PCR and western blot for GMFG, GMFG rescue experiment\",\n      \"journal\": \"Medical oncology (Northwood, London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, ubiquitination, transcriptomic identification, and epistatic rescue, single lab\",\n      \"pmids\": [\"35103856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF144A interacts with STING and promotes K6-linked ubiquitination of STING at lysine K236, enhancing STING translocation from the ER to the Golgi and downstream innate immune signaling. The K236R STING mutant shows reduced activity in innate immune signaling. RNF144A does not affect RNA virus- or cytosolic RNA-triggered innate immune responses (negative finding for RNA sensing). Rnf144a-deficient cells and mice show impaired DNA virus-triggered signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with linkage-specific antibodies, K236R STING mutant analysis, RNF144A knockdown/overexpression with interferon signaling readouts, Rnf144a-deficient mouse model with DNA virus challenge\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical ubiquitination assay with site-specific mutagenesis, in vivo KO mouse model, and multiple orthogonal functional readouts\",\n      \"pmids\": [\"37955227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In hepatocellular carcinoma cells, RNF144A mediates ubiquitination of DNA-PKcs following combined radiation and topoisomerase I inhibitor treatment, reducing DNA-PKcs prosurvival signaling. In PLC5 cells, RNF144A undergoes nuclear translocation and is decreased, correlating with DNA-PKcs accumulation and radioresistance. The ubiquitin/proteasome system is required for this effect (reversed by proteasome inhibition).\",\n      \"method\": \"Western blotting, immunoprecipitation, subcellular fractionation, confocal microscopy, proteasome inhibitor treatment\",\n      \"journal\": \"Journal of clinical and translational hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — immunoprecipitation and fractionation in cell lines, single lab, limited mechanistic follow-up; extends prior DNA-PKcs finding to hepatocellular carcinoma context\",\n      \"pmids\": [\"36969901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF144A interacts with BECN1 (Beclin-1) and promotes its K48-linked ubiquitination at K117 and K427, leading to proteasomal degradation of BECN1 and reduced autophagosome accumulation. This inhibits autophagy during L. monocytogenes infection. These two ubiquitination sites on BECN1 are required for the functional effect on autophagy and bacterial infection. rnf144a-deficient mice are protected from Lm infection and show enhanced innate immune responses.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with K48-linkage-specific antibodies, site-directed mutagenesis of BECN1 ubiquitination sites (K117R, K427R), autophagosome flux assays, rnf144a KO mouse model with L. monocytogenes infection, proximity ligation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in-cell ubiquitination with linkage-specific antibodies, site-specific mutagenesis of substrate, in vivo KO mouse infection model, multiple orthogonal methods\",\n      \"pmids\": [\"39608349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXF2 transcriptionally activates RNF144A expression, and the resulting RNF144A protein promotes ubiquitination and proteasomal degradation of FTO (an m6A demethylase). This axis contributes to suppression of M2 macrophage (TAM) polarization in esophageal squamous cell carcinoma.\",\n      \"method\": \"Overexpression/knockdown of FOXF2 and RNF144A with FTO protein-level readouts, ubiquitination assays, macrophage polarization assays, promoter transcription analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in-cell ubiquitination and functional rescue assays, single lab, identifies FTO as a new substrate\",\n      \"pmids\": [\"39447407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF144A promotes proteasomal degradation of VRK2, which reduces VRK2-mediated phosphorylation of G3BP1, thereby promoting stress granule (SG) assembly. Overexpression of VRK2 inhibits SG formation and sensitizes cells to stress and chemotherapy. This establishes an RNF144A–VRK2–G3BP1 axis regulating SG formation.\",\n      \"method\": \"VRK2 overexpression/knockdown, RNF144A overexpression with VRK2 protein-level readouts, G3BP1 phosphorylation assays, stress granule imaging, cell viability under chemotherapy\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in-cell degradation assays, phosphorylation readout, SG imaging with functional chemotherapy sensitivity, single lab\",\n      \"pmids\": [\"40204710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF144A interacts with thyroid-stimulating hormone receptor (TSHR) and promotes its ubiquitination and destabilization in lung fibroblasts. MSC-derived exosomes increase RNF144A expression, which suppresses TSHR protein levels and protects against LPS-induced pneumonia in vitro and in vivo. Re-expression of TSHR reverses the protective effects of MSC exosomes.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, immunoprecipitation, RNF144A knockdown with TSHR protein-level readouts, LPS pneumonia mouse model\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — GST pull-down plus co-IP plus in vivo model, single lab, identifies TSHR as a new substrate\",\n      \"pmids\": [\"41123861\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF144A is a single-pass transmembrane RBR (RING1-IBR-RING2) E3 ubiquitin ligase that localizes to cytoplasmic vesicles and the plasma membrane via its TM domain; its ligase activity requires both membrane localization and TM domain-mediated self-association through a GXXXG motif. It is transcriptionally induced by p53 following DNA damage and can be epigenetically silenced by promoter hypermethylation via MBD4. RNF144A ubiquitinates and promotes proteasomal degradation of multiple substrates including DNA-PKcs (K48-linked, apoptosis during DNA damage), PARP1, HSPA2, PD-L1, BMI1, LIN28B, YY1, VRK3, VRK2, BECN1 (K48-linked at K117/K427, suppressing autophagy), FTO, and TSHR; it also promotes K6-linked ubiquitination of STING at K236 to enhance its ER-to-Golgi translocation and antiviral innate immune signaling. Through regulated substrate degradation, RNF144A controls DNA repair signaling, EGF/EGFR pathway activity, ERK-dependent apoptosis, stress granule assembly, autophagy, and innate immune responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF144A is a membrane-anchored RBR (RING1-IBR-RING2) E3 ubiquitin ligase that controls diverse cellular programs by directing substrates to proteasomal degradation, including DNA repair signaling, growth-factor signaling, apoptosis, autophagy, and innate immunity [#0, #8, #11, #13]. Its catalytic RING module coordinates two zinc atoms and presents the active site and E2-binding interface [#6], while a C-terminal transmembrane (TM) domain performs two distinct functions: it targets RNF144A to cytoplasmic vesicles and the plasma membrane and, through self-association via a GXXXG (G252XXXG256) motif, activates ligase activity—mutation of these glycines preserves membrane localization but abolishes both self-association and catalysis [#0, #1]. RNF144A is transcriptionally induced by p53 after DNA damage and can be epigenetically silenced by promoter CpG hypermethylation acting through MBD4 [#0, #4]. Through K48-linked ubiquitination it degrades DNA-PKcs to sensitize cells to DNA damage-induced apoptosis [#0, #12] and degrades BECN1 at K117/K427 to suppress autophagy during bacterial infection [#13]; it likewise drives degradation of PARP1, HSPA2, PD-L1, BMI1, LIN28B, YY1, VRK3, VRK2, FTO, and TSHR, coupling its ligase output to PARP-inhibitor sensitivity, tumor-immune surveillance, ERK-dependent apoptosis, and stress granule assembly [#2, #5, #7, #8, #9, #10, #15]. In contrast to its degradative activity, RNF144A promotes non-degradative K6-linked ubiquitination of STING at K236 to enhance ER-to-Golgi translocation and DNA virus-triggered antiviral signaling [#11]. RNF144A also stabilizes EGFR and prolongs EGF/EGFR signaling during ligand stimulation, indicating that its ubiquitination outputs are substrate- and stimulus-dependent rather than uniformly destabilizing [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established RNF144A as a functional RBR E3 ligase with a defined substrate and biological role, answering whether this protein has catalytic ubiquitination activity and what it does.\",\n      \"evidence\": \"In vitro ubiquitination, co-IP, subcellular fractionation, and p53-dependent expression analysis showing RNF144A degrades DNA-PKcs and sensitizes to DNA damage apoptosis\",\n      \"pmids\": [\"24979766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type on DNA-PKcs not fully resolved at this stage\", \"Mechanism of vesicle/plasma membrane targeting not yet defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how the TM domain governs activity, showing that membrane targeting and GXXXG-mediated self-association are separable and that self-association is required for full ligase activity.\",\n      \"evidence\": \"TM/GXXXG deletion and point mutagenesis (G252L/G256L, G252D) with in vitro ubiquitination, membrane fractionation, and co-IP for self-association\",\n      \"pmids\": [\"26216882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TM self-association not determined\", \"How self-association allosterically activates the catalytic RBR module is unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the substrate repertoire to PARP1 and linked RNF144A levels to chemotherapy response, addressing how RNF144A modulates PARP-inhibitor sensitivity.\",\n      \"evidence\": \"Reciprocal co-IP, K48-linked in-cell ubiquitination assays, and olaparib sensitivity assays in breast cancer cells\",\n      \"pmids\": [\"29212245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no in vivo confirmation\", \"Direct ubiquitination site on PARP1 not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed RNF144A is not uniformly degradative, revealing a stimulus-dependent role in stabilizing EGFR and prolonging EGF/EGFR signaling.\",\n      \"evidence\": \"Knockdown/knockout with EGFR protein-level and signaling readouts, co-IP, proliferation and G1/S gene expression assays\",\n      \"pmids\": [\"30171075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type stabilizing EGFR not defined\", \"How the same ligase stabilizes some substrates while degrading others mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified an epigenetic mechanism silencing RNF144A in cancer, answering how its expression is lost in tumors.\",\n      \"evidence\": \"Bisulfite methylation analysis, 5-Aza-2-deoxycytidine reactivation, and MBD4 knockdown/inhibition with RNF144A expression readouts\",\n      \"pmids\": [\"29473320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MBD4 binding to the RNF144A promoter not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Used unbiased proteomics to identify HSPA2 as a substrate and tied catalytic activity to tumor suppression via rescue epistasis.\",\n      \"evidence\": \"Quantitative proteomics, ligase-dead mutagenesis, in-cell ubiquitination, and HSPA2 rescue with in vitro and in vivo tumor assays\",\n      \"pmids\": [\"31406303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HSPA2 ubiquitination sites not mapped\", \"Linkage type not specified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided atomic-resolution detail of the catalytic RING domain, defining zinc coordination and the E2-binding interface.\",\n      \"evidence\": \"Solution NMR structure of the RING finger domain and metallochromic zinc stoichiometry assay\",\n      \"pmids\": [\"32557973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length or IBR/RING2 structure not determined\", \"No structure of substrate- or E2-bound complex\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected RNF144A to ERK-dependent apoptosis through stress-regulated degradation of VRK3.\",\n      \"evidence\": \"Co-IP, in-cell ubiquitination, oxidative-stress fractionation, and RNF144A perturbation with VRK3/ERK and apoptosis readouts\",\n      \"pmids\": [\"33067254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"VRK3 ubiquitination sites and linkage not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established an in vivo immunoregulatory role, showing RNF144A degrades PD-L1 (and BMI1) and shapes tumor-infiltrating CD8+ T cells.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and Rnf144a knockout mice challenged with carcinogen (BBN) with IHC/flow cytometry for CD8+ T cells\",\n      \"pmids\": [\"34400221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BMI1 mechanism less developed than PD-L1\", \"PD-L1 ubiquitination sites not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added LIN28B as a substrate linking RNF144A to stem-cell pluripotency programs in ovarian cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, LIN28B rescue of pluripotency markers, and xenograft model\",\n      \"pmids\": [\"33978933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct versus indirect ubiquitination of LIN28B not fully distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RNF144A controls transcription indirectly by degrading the factor YY1 and blocking GMFG activation.\",\n      \"evidence\": \"Co-IP, ubiquitination, transcriptome profiling, and GMFG rescue in breast cancer cells\",\n      \"pmids\": [\"35103856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"YY1 ubiquitination site not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-degradative ubiquitination output, with K6-linked ubiquitination of STING at K236 promoting ER-to-Golgi translocation and DNA-virus antiviral signaling.\",\n      \"evidence\": \"Linkage-specific ubiquitination assays, K236R mutant analysis, and Rnf144a-deficient mice with DNA virus challenge; negative result for RNA sensing\",\n      \"pmids\": [\"37955227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for K6 versus K48 linkage selection unknown\", \"How membrane-localized RNF144A engages STING at the ER not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended DNA-PKcs targeting to hepatocellular carcinoma and linked RNF144A nuclear translocation/loss to radioresistance.\",\n      \"evidence\": \"Western blotting, IP, fractionation, confocal microscopy, and proteasome inhibitor treatment in HCC cells after radiation/topoisomerase inhibitor\",\n      \"pmids\": [\"36969901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism and signal driving nuclear translocation unresolved\", \"Limited mechanistic follow-up, single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined RNF144A as a suppressor of autophagy through site-specific K48 ubiquitination of BECN1 at K117/K427, with an in vivo anti-bacterial consequence.\",\n      \"evidence\": \"Linkage-specific ubiquitination, BECN1 K117R/K427R mutagenesis, autophagosome flux, PLA, and rnf144a KO mice infected with L. monocytogenes\",\n      \"pmids\": [\"39608349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How autophagy suppression integrates with STING-driven antiviral role not reconciled\", \"E2 partner for BECN1 ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed RNF144A within a FOXF2-driven transcriptional axis that degrades the m6A demethylase FTO to suppress M2 macrophage polarization.\",\n      \"evidence\": \"FOXF2/RNF144A perturbation with FTO readouts, ubiquitination assays, macrophage polarization, and promoter transcription analysis\",\n      \"pmids\": [\"39447407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FTO ubiquitination sites not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an RNF144A-VRK2-G3BP1 axis regulating stress granule assembly and chemotherapy sensitivity.\",\n      \"evidence\": \"RNF144A-driven VRK2 degradation, G3BP1 phosphorylation readouts, stress granule imaging, and viability assays under chemotherapy\",\n      \"pmids\": [\"40204710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of VRK2 by RNF144A versus indirect effect not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added TSHR as a substrate in lung fibroblasts and connected MSC-exosome-induced RNF144A to protection from LPS pneumonia.\",\n      \"evidence\": \"GST pull-down, co-IP, knockdown with TSHR readouts, and LPS pneumonia mouse model with TSHR rescue\",\n      \"pmids\": [\"41123861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TSHR ubiquitination sites and linkage not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what determines RNF144A linkage-type selection (K48 degradative versus K6 non-degradative) and substrate choice across its many reported targets, and how its membrane localization is reconciled with action on nuclear, cytosolic, and ER-resident substrates.\",\n      \"evidence\": \"No timeline study systematically defines the structural/regulatory determinants of linkage specificity or substrate selection\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism for linkage choice\", \"Cofactors/adaptors governing substrate selection unidentified\", \"Relationship between subcellular targeting and substrate access unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 5, 11, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 8, 11, 13]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 8, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 11, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DNA-PKcs (PRKDC)\", \"EGFR\", \"PARP1\", \"HSPA2\", \"PD-L1 (CD274)\", \"STING (TMEM173)\", \"BECN1\", \"VRK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}