{"gene":"DDRGK1","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2011,"finding":"DDRGK1 (UFBP1) localizes to the endoplasmic reticulum in a UFBP1-dependent manner and interacts with UFM1. siRNA-mediated knockdown of Ufbp1 or Ufm1 enhances apoptosis upon ER stress in pancreatic beta cells, and silencing the E3 enzyme UFL1 produces the same outcome, indicating that UFM1-UFBP1 conjugation is required to prevent ER stress-induced apoptosis.","method":"Co-localization by immunofluorescence, co-immunoprecipitation, siRNA knockdown with apoptosis readout","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown with defined apoptosis phenotype, single lab, multiple orthogonal methods","pmids":["21494687"],"is_preprint":false},{"year":2010,"finding":"DDRGK1 interacts with C53/LZAP (CDK5RAP3) and with RCAD (UFL1) as part of a large protein complex. RCAD knockdown leads to proteasome-mediated degradation of both C53/LZAP and DDRGK1, while RCAD overexpression attenuates their ubiquitination, indicating RCAD stabilizes DDRGK1 by protecting it from proteasomal degradation.","method":"Co-immunoprecipitation, gel filtration, proteasome inhibitor experiments, ubiquitination assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, gel filtration, and functional ubiquitination assays in single lab with multiple orthogonal methods","pmids":["20228063"],"is_preprint":false},{"year":2013,"finding":"DDRGK1 interacts with IκBα and regulates its stability, thereby modulating NF-κB transcriptional activity. Depletion of DDRGK1 inhibits NF-κB target gene expression and reduces cell proliferation and invasion.","method":"Co-immunoprecipitation, microarray analysis of NF-κB targets, siRNA knockdown with proliferation/invasion assays","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with functional follow-up, single lab, single method for binding","pmids":["23675531"],"is_preprint":false},{"year":2017,"finding":"DDRGK1 is an ER membrane protein that stabilizes the ER-stress sensor IRE1α by interacting with the kinase domain of IRE1α, protecting it from degradation. This interaction is dependent on DDRGK1's ufmylation modification. Depletion of DDRGK1 represses IRE1α-XBP1 signaling and activates the PERK-eIF2α-CHOP apoptotic pathway.","method":"Co-immunoprecipitation (DDRGK1 with IRE1α kinase domain), siRNA knockdown, ufmylation mutant analysis, UPR pathway readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying specific domain, ufmylation-dependence established by mutant, multiple UPR pathway readouts, independently replicated in subsequent papers","pmids":["28128204"],"is_preprint":false},{"year":2017,"finding":"DDRGK1 directly binds SOX9 and inhibits its ubiquitination and proteasomal degradation. Loss of DDRGK1 in zebrafish and mouse models decreases SOX9 protein levels and causes defective chondrogenesis; overexpression of sox9 rescues the chondrogenic phenotype caused by ddrgk1 knockdown.","method":"Co-immunoprecipitation (DDRGK1-SOX9 binding), ubiquitination assay, zebrafish knockdown with genetic rescue, Ddrgk1-/- mouse model with SOX9/Col2a1 readouts","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay, ubiquitination protection demonstrated in vitro, genetic rescue in zebrafish, mouse KO with defined molecular phenotype, replicated in subsequent studies","pmids":["28263186"],"is_preprint":false},{"year":2015,"finding":"DDRGK1 (UFBP1) is required for embryonic development and hematopoiesis. UFBP1 deficiency causes elevated ER stress, activation of UPR, and cell death in hematopoietic stem/progenitor cells. Additionally, UFBP1 loss suppresses expression of erythroid transcription factors GATA-1 and KLF1, and the transcriptional co-activator ASC1 associates with GATA-1 and Klf1 promoters in a UFBP1-dependent manner.","method":"Germline and conditional knockout mouse models, ChIP for ASC1 at promoters, siRNA knockdown of Uba5 and ASC1 in K562 cells, UPR/ER stress assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline and conditional KO with defined phenotypes, ChIP demonstrating promoter association, mechanistic dissection with multiple genetic tools","pmids":["26544067"],"is_preprint":false},{"year":2019,"finding":"UFBP1 (DDRGK1) promotes plasma cell development by suppressing PERK activation, while the IRE1α/XBP1 axis upregulates UFBP1 expression. Structure-function analysis shows lysine 267 (the main ufmylation site) is required for immunoglobulin production and ER expansion in IRE1α-deficient plasmablasts but is dispensable for plasmablast development itself.","method":"Conditional knockout mice, UFBP1 K267R mutant knockin/overexpression, plasma cell differentiation assays, ER expansion measurements, immunoglobulin production assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, site-specific ufmylation mutant, multiple functional readouts across two cell types, single lab with orthogonal methods","pmids":["30842412"],"is_preprint":false},{"year":2018,"finding":"UFBP1 interacts with approximately 80 proteins (identified by IP-MS) and promotes ubiquitination and degradation of interacting proteins by enhancing their interaction with cognate E3 ligases. Using ANT3 as a model substrate, UFBP1 was shown to enhance the ANT3-E3 ligase interaction, promoting ANT3 ubiquitination and proteasomal degradation.","method":"Co-immunoprecipitation, label-free quantitative proteomics (IP-MS), proteasome inhibitor assays, protein synthesis inhibition assays, ubiquitination assays","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS for interactome, biochemical ubiquitination assay with model substrate ANT3, single lab with multiple orthogonal methods","pmids":["29533670"],"is_preprint":false},{"year":2020,"finding":"UFBP1 promotes K48-linked polyubiquitination and proteasomal degradation of NRF2, thereby suppressing NRF2-driven antioxidant gene expression (AKR1Cs) and enhancing cisplatin sensitivity in gastric cancer cells.","method":"SILAC quantitative proteomics, ubiquitination assay (K48-linkage specific), siRNA knockdown, overexpression, flow cytometry for ROS, in vivo xenograft experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K48-linkage specific ubiquitination assay, SILAC proteomics, in vitro and in vivo experiments, single lab","pmids":["33219317"],"is_preprint":false},{"year":2023,"finding":"DDRGK1 competitively binds KEAP1 to inhibit KEAP1-mediated ubiquitination and proteasomal degradation of NRF2, stabilizing NRF2 and promoting antioxidant responses. DDRGK1 knockout reduces NRF2 stability, causes ROS accumulation, and enhances chemosensitivity to doxorubicin and etoposide in osteosarcoma.","method":"Quantitative proteomics, co-immunoprecipitation (DDRGK1-KEAP1 competitive binding), DDRGK1 knockout (genetic), ROS measurement, in vivo xenograft experiments","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for competitive binding, KO with ROS and in vivo phenotype, single lab with multiple orthogonal methods; note this finding contradicts PMID:33219317 on NRF2 regulation direction","pmids":["36965071"],"is_preprint":false},{"year":2021,"finding":"DDRGK1 deficiency in MEFs has a dual effect on autophagy: it promotes autophagy induction by impairing mTOR signaling, while simultaneously blocking autophagosome-lysosome fusion. DDRGK1 loss is associated with suppressed lysosomal function including impaired Cathepsin D expression, aberrant lysosomal pH, and v-ATPase accumulation.","method":"Inducible conditional KO MEFs (4-OHT-driven CreERT2), autophagy flux assays, mTOR activity readouts, lysosomal pH measurement, Cathepsin D assays, v-ATPase analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible genetic KO with defined molecular phenotypes across multiple lysosomal readouts, single lab","pmids":["33879777"],"is_preprint":false},{"year":2023,"finding":"The UFL1/UFBP1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates mTOR signaling, driving hepatocellular carcinoma development.","method":"Co-immunoprecipitation (Ufl1/Ufbp1 with mTOR/GβL), hepatocyte-specific conditional KO mice, iTRAQ proteomics, HCC tumor models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP of complex, conditional KO with defined HCC phenotype, single lab","pmids":["37131258"],"is_preprint":false},{"year":2023,"finding":"Loss of DDRGK1 decreases UFMylation of IRE1α and leads to increased ubiquitylation-mediated IRE1α degradation in chondrocytes, causing ER dysfunction and activating the PERK/CHOP/Caspase3 apoptosis pathway. DDRGK1 K268R-mutant mice confirm the importance of K268 UFMylation for IRE1α stability in vivo.","method":"Conditional KO mice (Col2a1-ERT Cre), DDRGK1 K268R knockin mice, UFMylation and ubiquitylation assays, PERK/CHOP/Caspase3 pathway analysis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific knockin mutant in vivo, UFMylation/ubiquitylation competitive modification assay, single lab","pmids":["37781516"],"is_preprint":false},{"year":2021,"finding":"UFBP1 directly binds Smad3 (demonstrated by endogenous co-immunoprecipitation) and suppresses Smad3 phosphorylation. UFBP1 deficiency leads to increased Smad3 phosphorylation and nuclear translocation, without affecting Smad2 phosphorylation, contributing to hepatic fibrosis.","method":"Endogenous co-immunoprecipitation (UFBP1-Smad3), conditional KO mice, UFBP1 overexpression in HeLa cells, phospho-Smad2/3 analysis","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single endogenous Co-IP for binding, functional data from KO and overexpression, single lab, single binding method","pmids":["34307359"],"is_preprint":false},{"year":2024,"finding":"DDRGK1-UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Overexpression of DDRGK1 in HK-2 cells enhances ER-phagy levels and ameliorates contrast-induced ER stress and apoptosis.","method":"DDRGK1 overexpression in HK-2 cells, four murine AKI models, ER-phagy flux assays, ER stress and apoptosis markers","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with functional readout, no direct mechanistic dissection of ER-phagy receptor function, single lab","pmids":["38233375"],"is_preprint":false},{"year":2023,"finding":"Ufmylation on UFBP1 (at K267) is required for alleviating ER stress-dependent lipogenesis in hepatocytes. Wild-type UFBP1 but not UFBP1 K267R mutant rescues lipid accumulation caused by UFBP1 knockdown, and ufmylation on UFBP1 ameliorates hepatic steatosis, dyslipidemia, and insulin resistance in vivo.","method":"UFBP1 K267R knockin/rescue experiments in vitro, HFD mouse model with WT vs. K267R UFBP1, ER stress markers, lipid accumulation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ufmylation mutant rescue experiments in vitro and in vivo, single lab with multiple metabolic readouts","pmids":["37660122"],"is_preprint":false},{"year":2023,"finding":"UFBP1 K268 ufmylation is dispensable for ER stress response in mouse embryonic fibroblasts, embryonic development, cardiac homeostasis, and intestinal homeostasis under DSS-induced colitis. The K268R knockin mutation reduces total ufmylated proteins without altering ER stress signaling or causing morphological abnormalities up to one year of age.","method":"UFBP1 K268R knockin mice, MEF ER stress assays, serial echocardiography, DSS-induced colitis model","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockin mouse model with multiple orthogonal phenotypic readouts, negative findings rigorously established, single lab","pmids":["37566002"],"is_preprint":false},{"year":2009,"finding":"DDRGK1 (Dashurin/C20orf116) contains a C-terminal PCI domain. Cell compartment fractionation showed presence in peroxisomes/mitochondria, microsomes, cytosol, and nucleus. GFP-Dashurin fusion protein shuttles between cytosol and nucleus. Luciferase reporter assays showed 2-3 fold increase in promoter activity upon overexpression.","method":"Cell fractionation, GFP fusion protein live imaging, luciferase reporter assay","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method localization by fractionation and GFP imaging without functional consequence, single lab","pmids":["20036718"],"is_preprint":false},{"year":2026,"finding":"XIAP binds to DDRGK1 and increases DDRGK1 protein stability, activating ER-phagy. Noise exposure reduces both XIAP and DDRGK1 protein levels in cochlear cells; gastrodin promotes XIAP expression, increasing DDRGK1 levels and activating ER-phagy to protect cochlear hair cells.","method":"Co-immunoprecipitation (XIAP-DDRGK1), DDRGK1 stability assays, ER-phagy flux assays, in vivo CBA/CaJ mouse noise exposure model","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for XIAP-DDRGK1 binding, functional data in vitro and in vivo, single lab, limited mechanistic detail in abstract","pmids":["41588674"],"is_preprint":false},{"year":2026,"finding":"DDRGK1 acts as a UFMylation effector that stabilizes FASN by competitively inhibiting its ubiquitination. DDRGK1 K268R mutant mice show reduced FASN protein and are protected from HFD-induced obesity, with 12% reduced body weight and 18% decreased fat mass.","method":"DDRGK1 K268R knockin mice, HFD model, FASN ubiquitination competitive assay, single-nucleus RNA sequencing, lipidomics, in vitro adipocyte lipid droplet assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific knockin in vivo, competitive ubiquitination assay, multi-omic readouts, single lab","pmids":["41671397"],"is_preprint":false},{"year":2026,"finding":"DDRGK1 directly interacts with and stabilizes IP3R (inositol trisphosphate receptor), preventing its ubiquitin-mediated degradation. DDRGK1 deficiency reduces IP3R protein levels, impairing mitochondrial calcium uptake and oxidative phosphorylation, and activating CHOP while suppressing PGC-1α-mediated mitochondrial biogenesis.","method":"Co-immunoprecipitation (DDRGK1-IP3R), ubiquitination assays, respirometry, ATP measurements, calcium uptake assays, CHOP/PGC-1α pathway analysis","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — direct binding by Co-IP and ubiquitination protection assay, multiple bioenergetic readouts, single lab, abstract only","pmids":["42171880"],"is_preprint":false},{"year":2024,"finding":"Depletion of DDRGK1 (along with UFL1 and UFM1) in human macrophages results in increased IFN-β production and secretion during Mycobacterium marinum and M. tuberculosis infection, indicating that UFMylation activity (including DDRGK1) is required to suppress Type I IFN signaling during mycobacterial infection.","method":"Genome-wide CRISPRi screen in human macrophages, siRNA depletion of DDRGK1, IFN-β ELISA, transcriptional profiling","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CRISPRi screen hit with siRNA validation, single functional readout, preprint not peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"DDRGK1 (UFBP1) is an ER-localized adaptor protein and core component of the UFM1 conjugation system that stabilizes multiple client proteins—including IRE1α, SOX9, NRF2/FASN, IP3R, and IκBα—by protecting them from ubiquitin-proteasomal degradation, thereby maintaining ER homeostasis (via IRE1α-XBP1 signaling), regulating chondrogenesis, hematopoiesis, and plasma cell development; its own stability and functions are modulated by ufmylation (primarily at K267/K268), and it functions within a UFL1/UFBP1 complex that also attenuates mTORC1 activity and suppresses Type I IFN signaling."},"narrative":{"mechanistic_narrative":"DDRGK1 (UFBP1) is an endoplasmic reticulum membrane protein that serves as a core component and substrate adaptor of the UFM1 conjugation (ufmylation) system, governing ER homeostasis and the stability of multiple client proteins [PMID:21494687, PMID:28128204]. Within a UFL1/UFBP1 complex it both transfers UFM1 and is itself ufmylated, and its own stability is maintained by UFL1, which protects it from proteasomal degradation [PMID:20228063]. A recurrent theme across its targets is control of client protein turnover: DDRGK1 stabilizes the ER-stress sensor IRE1α by binding its kinase domain in a ufmylation-dependent manner, sustaining IRE1α-XBP1 signaling and suppressing the PERK-eIF2α-CHOP apoptotic arm [PMID:28128204, PMID:37781516]. The same protective logic extends to the chondrogenic master regulator SOX9, whose ubiquitination DDRGK1 blocks to drive cartilage development [PMID:28263186], and to FASN and IP3R, which DDRGK1 stabilizes by competitively inhibiting their ubiquitination [PMID:41671397, PMID:42171880]. Through these activities DDRGK1 controls embryonic development and hematopoiesis, where its loss elevates ER stress and represses erythroid transcription factors via ASC1-dependent promoter association [PMID:26544067], and promotes plasma cell development by restraining PERK [PMID:30842412]. Site-specific ufmylation of DDRGK1 (K267/K268) is required for several functions including IRE1α stabilization, control of hepatic lipogenesis, and FASN-dependent adiposity [PMID:37781516, PMID:37660122, PMID:41671397], though this modification is dispensable for embryonic, cardiac, and intestinal homeostasis [PMID:37566002]. The UFL1/UFBP1 complex additionally attenuates mTORC1 by directly engaging the mTOR/GβL complex [PMID:37131258], and DDRGK1 modulates autophagy and ER-phagy [PMID:33879777, PMID:38233375]. Reported effects on NRF2 stability are conflicting, with evidence for both promoting [PMID:33219317] and inhibiting [PMID:36965071] its degradation.","teleology":[{"year":2010,"claim":"Established DDRGK1 as a stable member of a UFL1 (RCAD)/CDK5RAP3 (C53/LZAP) protein complex and showed its abundance is set by UFL1-dependent protection from proteasomal degradation, defining the molecular context for its later adaptor roles.","evidence":"Co-IP, gel filtration, and ubiquitination assays with proteasome inhibition","pmids":["20228063"],"confidence":"Medium","gaps":["Did not define the E3 ligase responsible for DDRGK1 ubiquitination","Did not connect complex assembly to ufmylation enzymology"]},{"year":2011,"claim":"Placed DDRGK1 at the ER as a UFM1-conjugation partner required to prevent ER-stress-induced apoptosis, linking the ufmylation machinery (UFM1, UFL1, UFBP1) to ER homeostasis.","evidence":"Immunofluorescence co-localization, reciprocal Co-IP, and siRNA knockdown with apoptosis readout in pancreatic beta cells","pmids":["21494687"],"confidence":"Medium","gaps":["No molecular target of the protective effect identified","Mechanism connecting ufmylation to apoptosis suppression unresolved"]},{"year":2013,"claim":"Proposed DDRGK1 regulates NF-κB signaling by controlling IκBα stability, extending its client-stabilization role to inflammatory transcription.","evidence":"Co-IP, NF-κB target microarray, and siRNA knockdown with proliferation/invasion assays","pmids":["23675531"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation for IκBα binding","Direction and mechanism of stability control not biochemically dissected"]},{"year":2015,"claim":"Demonstrated DDRGK1 is essential for embryonic development and hematopoiesis in vivo, tying ER-stress control to stem/progenitor survival and erythroid transcription factor expression.","evidence":"Germline and conditional KO mice, ChIP for ASC1 at GATA-1/KLF1 promoters, siRNA in K562 cells","pmids":["26544067"],"confidence":"High","gaps":["How UFBP1 controls ASC1 promoter recruitment mechanistically unclear","Direct versus indirect regulation of GATA-1/KLF1 not fully separated"]},{"year":2017,"claim":"Defined the key mechanistic principle that DDRGK1 stabilizes IRE1α by binding its kinase domain in a ufmylation-dependent manner, balancing the IRE1α-XBP1 versus PERK-CHOP arms of the UPR.","evidence":"Domain-mapped Co-IP, siRNA knockdown, ufmylation mutant analysis, UPR pathway readouts","pmids":["28128204"],"confidence":"High","gaps":["The E3 ligase degrading IRE1α in DDRGK1's absence not identified","Structural basis of kinase-domain recognition unresolved"]},{"year":2017,"claim":"Showed DDRGK1 directly binds and protects SOX9 from ubiquitination, establishing a developmental client and a genetic role in chondrogenesis confirmed by rescue.","evidence":"Co-IP, ubiquitination assay, zebrafish knockdown with sox9 rescue, Ddrgk1-/- mouse with SOX9/Col2a1 readouts","pmids":["28263186"],"confidence":"High","gaps":["Whether SOX9 protection requires DDRGK1 ufmylation not established here","E3 ligase acting on SOX9 not identified"]},{"year":2018,"claim":"Reframed DDRGK1 as a broad interactome hub that, contrary to its IRE1α/SOX9 stabilizing role, can promote client ubiquitination by enhancing substrate-E3 ligase engagement.","evidence":"IP-MS interactome (~80 proteins), ubiquitination assays using ANT3 as model substrate","pmids":["29533670"],"confidence":"Medium","gaps":["What determines whether DDRGK1 stabilizes versus degrades a client unresolved","Which E3 ligases are recruited not systematically mapped"]},{"year":2019,"claim":"Identified UFBP1 ufmylation at K267 as functionally required for immunoglobulin production and ER expansion in plasma cells, while showing it promotes plasma cell development by suppressing PERK in a feedback loop with IRE1α/XBP1.","evidence":"Conditional KO mice, K267R mutant, plasma cell differentiation and immunoglobulin assays","pmids":["30842412"],"confidence":"High","gaps":["Downstream effectors of K267 ufmylation in ER expansion not defined","Distinction between K267 ufmylation-dependent and -independent functions partial"]},{"year":2020,"claim":"Reported UFBP1 promotes K48-linked ubiquitination and degradation of NRF2, suppressing antioxidant gene expression and sensitizing gastric cancer cells to cisplatin.","evidence":"SILAC proteomics, K48-linkage ubiquitination assay, knockdown/overexpression, ROS flow cytometry, xenografts","pmids":["33219317"],"confidence":"Medium","gaps":["Directly contradicts later report of NRF2 stabilization (idx 9)","E3 ligase mediating NRF2 degradation not specified"]},{"year":2021,"claim":"Revealed a dual, opposing role of DDRGK1 in autophagy: it restrains mTOR to permit autophagy induction while being required for autophagosome-lysosome fusion and lysosomal function.","evidence":"Inducible conditional KO MEFs, autophagy flux and mTOR assays, lysosomal pH, Cathepsin D, v-ATPase analysis","pmids":["33879777"],"confidence":"Medium","gaps":["Molecular link between DDRGK1 and lysosomal acidification machinery unknown","Whether mTOR and fusion effects are mechanistically connected unclear"]},{"year":2021,"claim":"Proposed DDRGK1 binds Smad3 and suppresses its phosphorylation, limiting hepatic fibrosis through a TGF-β/Smad-restraining role distinct from its degradation functions.","evidence":"Endogenous Co-IP, conditional KO mice, overexpression, phospho-Smad2/3 analysis","pmids":["34307359"],"confidence":"Low","gaps":["Single endogenous Co-IP without reciprocal validation","Mechanism of selective Smad3 (not Smad2) phospho-suppression unresolved"]},{"year":2023,"claim":"Confirmed in vivo, with K268R knockin mice, that DDRGK1 ufmylation drives IRE1α ufmylation and protection from ubiquitin-mediated degradation in chondrocytes, validating the modification's physiological importance.","evidence":"Conditional KO and K268R knockin mice, UFMylation/ubiquitylation competitive assays, PERK/CHOP/Caspase3 analysis","pmids":["37781516"],"confidence":"Medium","gaps":["How IRE1α ufmylation status determines its ubiquitination not biochemically resolved","Tissue-specificity of K268 requirement unclear"]},{"year":2023,"claim":"Showed the UFL1/UFBP1 complex directly binds the mTOR/GβL complex to attenuate mTORC1 activity, with loss driving hepatocellular carcinoma, providing a direct molecular basis for the earlier mTOR/autophagy phenotype.","evidence":"Co-IP of the complex, hepatocyte conditional KO mice, iTRAQ proteomics, HCC tumor models","pmids":["37131258"],"confidence":"Medium","gaps":["Whether mTOR attenuation requires ufmylation activity unclear","Direct site of mTOR/GβL engagement not mapped"]},{"year":2023,"claim":"Reported the opposite of the 2020 NRF2 finding: DDRGK1 competitively binds KEAP1 to stabilize NRF2 and promote antioxidant responses, modulating chemosensitivity in osteosarcoma.","evidence":"Quantitative proteomics, competitive Co-IP, DDRGK1 KO, ROS measurement, xenografts","pmids":["36965071"],"confidence":"Medium","gaps":["Directly contradicts idx 8 on the direction of NRF2 regulation","Context dependence (cancer type) of the opposing effects unresolved"]},{"year":2023,"claim":"Established that UFBP1 ufmylation at K267 alleviates ER-stress-driven hepatic lipogenesis, linking the modification to metabolic disease phenotypes via rescue with WT but not K267R protein.","evidence":"K267R rescue in vitro, HFD mouse model with WT vs K267R UFBP1, ER stress and lipid assays","pmids":["37660122"],"confidence":"Medium","gaps":["Lipogenic effector downstream of K267 ufmylation not identified","Relationship to IRE1α/XBP1 axis in liver not dissected"]},{"year":2023,"claim":"Demonstrated that UFBP1 K268 ufmylation is dispensable for ER stress signaling, embryonic, cardiac, and intestinal homeostasis, sharpening the boundaries of where the modification is functionally required.","evidence":"K268R knockin mice, MEF ER stress assays, echocardiography, DSS colitis model","pmids":["37566002"],"confidence":"Medium","gaps":["Why K268 ufmylation matters in some tissues (chondrocytes, adipose) but not others unresolved","Compensatory ufmylation sites not excluded"]},{"year":2024,"claim":"Proposed DDRGK1-UFL1-mediated ER-phagy as a protective mechanism that mitigates ER stress and apoptosis in renal tubular cells.","evidence":"DDRGK1 overexpression in HK-2 cells, murine AKI models, ER-phagy flux assays","pmids":["38233375"],"confidence":"Low","gaps":["No direct mechanistic dissection of ER-phagy receptor function","Causal role of DDRGK1 versus correlation not separated"]},{"year":2024,"claim":"Implicated DDRGK1 and the UFMylation machinery in suppressing Type I IFN during mycobacterial infection in macrophages.","evidence":"Genome-wide CRISPRi screen with siRNA validation, IFN-β ELISA, transcriptional profiling (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint, not peer-reviewed","Single functional readout; molecular target of IFN suppression not identified"]},{"year":2026,"claim":"Extended DDRGK1's client-stabilization role to FASN, IP3R, and to upstream regulation by XIAP, connecting ufmylation to lipogenesis/adiposity, mitochondrial calcium/bioenergetics, and ER-phagy-mediated cochlear protection.","evidence":"K268R knockin mice with HFD and FASN ubiquitination assay; Co-IP and ubiquitination assays for IP3R; XIAP-DDRGK1 Co-IP with ER-phagy and noise-exposure models","pmids":["41671397","42171880","41588674"],"confidence":"Medium","gaps":["IP3R and XIAP findings are abstract/single-Co-IP level (Low confidence)","E3 ligases acting on FASN and IP3R not identified","Whether these stabilizations require DDRGK1 ufmylation not uniformly tested"]},{"year":null,"claim":"It remains unresolved what molecular feature determines whether DDRGK1 stabilizes a client (IRE1α, SOX9, FASN, IP3R) versus promotes its degradation (ANT3, NRF2 per idx 8), and the contradictory directionality of NRF2 regulation is unexplained.","evidence":"No timeline study reconciles the bidirectional adaptor behavior or the conflicting NRF2 results","pmids":[],"confidence":"Low","gaps":["No unifying biochemical model for substrate fate selection","E3 ligase recruitment specificity uncharacterized","Structural basis of client recognition unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,7,19]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,4,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,3,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,7,8,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]}],"complexes":["UFL1/UFBP1 (UFM1 E3 ligase) complex","UFL1/UFBP1/CDK5RAP3 (C53/LZAP) complex"],"partners":["UFL1","UFM1","CDK5RAP3","ERN1 (IRE1Α)","SOX9","KEAP1","MTOR","FASN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96HY6","full_name":"DDRGK domain-containing protein 1","aliases":["Dashurin","UFM1-binding and PCI domain-containing protein 1"],"length_aa":314,"mass_kda":35.6,"function":"Component of the UFM1 ribosome E3 ligase (UREL) complex, a multiprotein complex that catalyzes ufmylation of endoplasmic reticulum-docked proteins (PubMed:30626644, PubMed:32160526, PubMed:35753586, PubMed:36121123, PubMed:36543799, PubMed:37595036, PubMed:37795761, PubMed:38383785, PubMed:38383789). The UREL complex plays a key role in ribosome recycling by mediating mono-ufmylation of the RPL26/uL24 subunit of the 60S ribosome following ribosome dissociation: ufmylation weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane (PubMed:38383785, PubMed:38383789). Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum (PubMed:37595036, PubMed:38383785, PubMed:38383789). Within the UREL complex, DDRGK1 tethers the complex to the endoplasmic reticulum membrane to restrict its activity to endoplasmic reticulum-docked ribosomes and acts as an ufmylation 'reader': following RPL26/uL24 ufmylation, DDRGK1 specifically binds to ufmylated RPL26/uL24 via its UFIM motif, resulting in stable association between the 60S ribosome and the UREL complex, followed by dissociation of the 60S ribosome subunit from the endoplasmic reticulum membrane (PubMed:36121123, PubMed:37595036, PubMed:38383785, PubMed:38383789). The UREL complex is also involved in reticulophagy in response to endoplasmic reticulum stress by promoting ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins (PubMed:32160526, PubMed:36543799). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability (PubMed:28128204, PubMed:32160526). Acts as a regulator of immunity by promoting differentiation of B-cells into plasma cells: acts by promoting expansion of the endoplasmic reticulum and regulating the unfolded protein response (UPR) (By similarity). May also be required for TRIP4 ufmylation (PubMed:25219498). May play a role in NF-kappa-B-mediated transcription through regulation of the phosphorylation and the degradation of NFKBIA, the inhibitor of NF-kappa-B (PubMed:23675531). Plays a role in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator (PubMed:28263186). Required for stabilization and ufmylation of ATG9A (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96HY6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DDRGK1","classification":"Not Classified","n_dependent_lines":125,"n_total_lines":1208,"dependency_fraction":0.10347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMED10","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DDRGK1","total_profiled":1310},"omim":[{"mim_id":"616177","title":"DDRGK DOMAIN-CONTAINING PROTEIN 1; DDRGK1","url":"https://www.omim.org/entry/616177"},{"mim_id":"613372","title":"UFM1-SPECIFIC LIGASE 1; UFL1","url":"https://www.omim.org/entry/613372"},{"mim_id":"611482","title":"UFM1-SPECIFIC PEPTIDASE 2; UFSP2","url":"https://www.omim.org/entry/611482"},{"mim_id":"610554","title":"UBIQUITIN-FOLD MODIFIER-CONJUGATING ENZYME 1; UFC1","url":"https://www.omim.org/entry/610554"},{"mim_id":"610553","title":"UBIQUITIN-FOLD MODIFIER 1; UFM1","url":"https://www.omim.org/entry/610553"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDRGK1"},"hgnc":{"alias_symbol":["dJ1187M17.3","UFBP1"],"prev_symbol":["C20orf116"]},"alphafold":{"accession":"Q96HY6","domains":[{"cath_id":"1.10.10.10","chopping":"213-302","consensus_level":"medium","plddt":90.8918,"start":213,"end":302},{"cath_id":"1.20.5","chopping":"124-195","consensus_level":"medium","plddt":90.964,"start":124,"end":195}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HY6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HY6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HY6-F1-predicted_aligned_error_v6.png","plddt_mean":74.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDRGK1","jax_strain_url":"https://www.jax.org/strain/search?query=DDRGK1"},"sequence":{"accession":"Q96HY6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96HY6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96HY6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HY6"}},"corpus_meta":[{"pmid":"21494687","id":"PMC_21494687","title":"Ubiquitin 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dysplasia.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37781516","citation_count":13,"is_preprint":false},{"pmid":"35377455","id":"PMC_35377455","title":"DDRGK1 is required for the proper development and maintenance of the growth plate cartilage.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35377455","citation_count":13,"is_preprint":false},{"pmid":"34307359","id":"PMC_34307359","title":"Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34307359","citation_count":12,"is_preprint":false},{"pmid":"39551318","id":"PMC_39551318","title":"Bombyx mori UFBP1 regulates apoptosis and promotes BmNPV proliferation by affecting the expression of ER chaperone BmBIP.","date":"2024","source":"International 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RCAD knockdown leads to proteasome-mediated degradation of both C53/LZAP and DDRGK1, while RCAD overexpression attenuates their ubiquitination, indicating RCAD stabilizes DDRGK1 by protecting it from proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, gel filtration, proteasome inhibitor experiments, ubiquitination assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, gel filtration, and functional ubiquitination assays in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20228063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDRGK1 interacts with IκBα and regulates its stability, thereby modulating NF-κB transcriptional activity. Depletion of DDRGK1 inhibits NF-κB target gene expression and reduces cell proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation, microarray analysis of NF-κB targets, siRNA knockdown with proliferation/invasion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with functional follow-up, single lab, single method for binding\",\n      \"pmids\": [\"23675531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDRGK1 is an ER membrane protein that stabilizes the ER-stress sensor IRE1α by interacting with the kinase domain of IRE1α, protecting it from degradation. This interaction is dependent on DDRGK1's ufmylation modification. Depletion of DDRGK1 represses IRE1α-XBP1 signaling and activates the PERK-eIF2α-CHOP apoptotic pathway.\",\n      \"method\": \"Co-immunoprecipitation (DDRGK1 with IRE1α kinase domain), siRNA knockdown, ufmylation mutant analysis, UPR pathway readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying specific domain, ufmylation-dependence established by mutant, multiple UPR pathway readouts, independently replicated in subsequent papers\",\n      \"pmids\": [\"28128204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDRGK1 directly binds SOX9 and inhibits its ubiquitination and proteasomal degradation. Loss of DDRGK1 in zebrafish and mouse models decreases SOX9 protein levels and causes defective chondrogenesis; overexpression of sox9 rescues the chondrogenic phenotype caused by ddrgk1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation (DDRGK1-SOX9 binding), ubiquitination assay, zebrafish knockdown with genetic rescue, Ddrgk1-/- mouse model with SOX9/Col2a1 readouts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay, ubiquitination protection demonstrated in vitro, genetic rescue in zebrafish, mouse KO with defined molecular phenotype, replicated in subsequent studies\",\n      \"pmids\": [\"28263186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDRGK1 (UFBP1) is required for embryonic development and hematopoiesis. UFBP1 deficiency causes elevated ER stress, activation of UPR, and cell death in hematopoietic stem/progenitor cells. Additionally, UFBP1 loss suppresses expression of erythroid transcription factors GATA-1 and KLF1, and the transcriptional co-activator ASC1 associates with GATA-1 and Klf1 promoters in a UFBP1-dependent manner.\",\n      \"method\": \"Germline and conditional knockout mouse models, ChIP for ASC1 at promoters, siRNA knockdown of Uba5 and ASC1 in K562 cells, UPR/ER stress assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline and conditional KO with defined phenotypes, ChIP demonstrating promoter association, mechanistic dissection with multiple genetic tools\",\n      \"pmids\": [\"26544067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UFBP1 (DDRGK1) promotes plasma cell development by suppressing PERK activation, while the IRE1α/XBP1 axis upregulates UFBP1 expression. Structure-function analysis shows lysine 267 (the main ufmylation site) is required for immunoglobulin production and ER expansion in IRE1α-deficient plasmablasts but is dispensable for plasmablast development itself.\",\n      \"method\": \"Conditional knockout mice, UFBP1 K267R mutant knockin/overexpression, plasma cell differentiation assays, ER expansion measurements, immunoglobulin production assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, site-specific ufmylation mutant, multiple functional readouts across two cell types, single lab with orthogonal methods\",\n      \"pmids\": [\"30842412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UFBP1 interacts with approximately 80 proteins (identified by IP-MS) and promotes ubiquitination and degradation of interacting proteins by enhancing their interaction with cognate E3 ligases. Using ANT3 as a model substrate, UFBP1 was shown to enhance the ANT3-E3 ligase interaction, promoting ANT3 ubiquitination and proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, label-free quantitative proteomics (IP-MS), proteasome inhibitor assays, protein synthesis inhibition assays, ubiquitination assays\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS for interactome, biochemical ubiquitination assay with model substrate ANT3, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29533670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UFBP1 promotes K48-linked polyubiquitination and proteasomal degradation of NRF2, thereby suppressing NRF2-driven antioxidant gene expression (AKR1Cs) and enhancing cisplatin sensitivity in gastric cancer cells.\",\n      \"method\": \"SILAC quantitative proteomics, ubiquitination assay (K48-linkage specific), siRNA knockdown, overexpression, flow cytometry for ROS, in vivo xenograft experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K48-linkage specific ubiquitination assay, SILAC proteomics, in vitro and in vivo experiments, single lab\",\n      \"pmids\": [\"33219317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDRGK1 competitively binds KEAP1 to inhibit KEAP1-mediated ubiquitination and proteasomal degradation of NRF2, stabilizing NRF2 and promoting antioxidant responses. DDRGK1 knockout reduces NRF2 stability, causes ROS accumulation, and enhances chemosensitivity to doxorubicin and etoposide in osteosarcoma.\",\n      \"method\": \"Quantitative proteomics, co-immunoprecipitation (DDRGK1-KEAP1 competitive binding), DDRGK1 knockout (genetic), ROS measurement, in vivo xenograft experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for competitive binding, KO with ROS and in vivo phenotype, single lab with multiple orthogonal methods; note this finding contradicts PMID:33219317 on NRF2 regulation direction\",\n      \"pmids\": [\"36965071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDRGK1 deficiency in MEFs has a dual effect on autophagy: it promotes autophagy induction by impairing mTOR signaling, while simultaneously blocking autophagosome-lysosome fusion. DDRGK1 loss is associated with suppressed lysosomal function including impaired Cathepsin D expression, aberrant lysosomal pH, and v-ATPase accumulation.\",\n      \"method\": \"Inducible conditional KO MEFs (4-OHT-driven CreERT2), autophagy flux assays, mTOR activity readouts, lysosomal pH measurement, Cathepsin D assays, v-ATPase analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible genetic KO with defined molecular phenotypes across multiple lysosomal readouts, single lab\",\n      \"pmids\": [\"33879777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The UFL1/UFBP1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates mTOR signaling, driving hepatocellular carcinoma development.\",\n      \"method\": \"Co-immunoprecipitation (Ufl1/Ufbp1 with mTOR/GβL), hepatocyte-specific conditional KO mice, iTRAQ proteomics, HCC tumor models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP of complex, conditional KO with defined HCC phenotype, single lab\",\n      \"pmids\": [\"37131258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of DDRGK1 decreases UFMylation of IRE1α and leads to increased ubiquitylation-mediated IRE1α degradation in chondrocytes, causing ER dysfunction and activating the PERK/CHOP/Caspase3 apoptosis pathway. DDRGK1 K268R-mutant mice confirm the importance of K268 UFMylation for IRE1α stability in vivo.\",\n      \"method\": \"Conditional KO mice (Col2a1-ERT Cre), DDRGK1 K268R knockin mice, UFMylation and ubiquitylation assays, PERK/CHOP/Caspase3 pathway analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific knockin mutant in vivo, UFMylation/ubiquitylation competitive modification assay, single lab\",\n      \"pmids\": [\"37781516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UFBP1 directly binds Smad3 (demonstrated by endogenous co-immunoprecipitation) and suppresses Smad3 phosphorylation. UFBP1 deficiency leads to increased Smad3 phosphorylation and nuclear translocation, without affecting Smad2 phosphorylation, contributing to hepatic fibrosis.\",\n      \"method\": \"Endogenous co-immunoprecipitation (UFBP1-Smad3), conditional KO mice, UFBP1 overexpression in HeLa cells, phospho-Smad2/3 analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single endogenous Co-IP for binding, functional data from KO and overexpression, single lab, single binding method\",\n      \"pmids\": [\"34307359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDRGK1-UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Overexpression of DDRGK1 in HK-2 cells enhances ER-phagy levels and ameliorates contrast-induced ER stress and apoptosis.\",\n      \"method\": \"DDRGK1 overexpression in HK-2 cells, four murine AKI models, ER-phagy flux assays, ER stress and apoptosis markers\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with functional readout, no direct mechanistic dissection of ER-phagy receptor function, single lab\",\n      \"pmids\": [\"38233375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ufmylation on UFBP1 (at K267) is required for alleviating ER stress-dependent lipogenesis in hepatocytes. Wild-type UFBP1 but not UFBP1 K267R mutant rescues lipid accumulation caused by UFBP1 knockdown, and ufmylation on UFBP1 ameliorates hepatic steatosis, dyslipidemia, and insulin resistance in vivo.\",\n      \"method\": \"UFBP1 K267R knockin/rescue experiments in vitro, HFD mouse model with WT vs. K267R UFBP1, ER stress markers, lipid accumulation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ufmylation mutant rescue experiments in vitro and in vivo, single lab with multiple metabolic readouts\",\n      \"pmids\": [\"37660122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UFBP1 K268 ufmylation is dispensable for ER stress response in mouse embryonic fibroblasts, embryonic development, cardiac homeostasis, and intestinal homeostasis under DSS-induced colitis. The K268R knockin mutation reduces total ufmylated proteins without altering ER stress signaling or causing morphological abnormalities up to one year of age.\",\n      \"method\": \"UFBP1 K268R knockin mice, MEF ER stress assays, serial echocardiography, DSS-induced colitis model\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockin mouse model with multiple orthogonal phenotypic readouts, negative findings rigorously established, single lab\",\n      \"pmids\": [\"37566002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DDRGK1 (Dashurin/C20orf116) contains a C-terminal PCI domain. Cell compartment fractionation showed presence in peroxisomes/mitochondria, microsomes, cytosol, and nucleus. GFP-Dashurin fusion protein shuttles between cytosol and nucleus. Luciferase reporter assays showed 2-3 fold increase in promoter activity upon overexpression.\",\n      \"method\": \"Cell fractionation, GFP fusion protein live imaging, luciferase reporter assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method localization by fractionation and GFP imaging without functional consequence, single lab\",\n      \"pmids\": [\"20036718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"XIAP binds to DDRGK1 and increases DDRGK1 protein stability, activating ER-phagy. Noise exposure reduces both XIAP and DDRGK1 protein levels in cochlear cells; gastrodin promotes XIAP expression, increasing DDRGK1 levels and activating ER-phagy to protect cochlear hair cells.\",\n      \"method\": \"Co-immunoprecipitation (XIAP-DDRGK1), DDRGK1 stability assays, ER-phagy flux assays, in vivo CBA/CaJ mouse noise exposure model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for XIAP-DDRGK1 binding, functional data in vitro and in vivo, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"41588674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DDRGK1 acts as a UFMylation effector that stabilizes FASN by competitively inhibiting its ubiquitination. DDRGK1 K268R mutant mice show reduced FASN protein and are protected from HFD-induced obesity, with 12% reduced body weight and 18% decreased fat mass.\",\n      \"method\": \"DDRGK1 K268R knockin mice, HFD model, FASN ubiquitination competitive assay, single-nucleus RNA sequencing, lipidomics, in vitro adipocyte lipid droplet assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific knockin in vivo, competitive ubiquitination assay, multi-omic readouts, single lab\",\n      \"pmids\": [\"41671397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DDRGK1 directly interacts with and stabilizes IP3R (inositol trisphosphate receptor), preventing its ubiquitin-mediated degradation. DDRGK1 deficiency reduces IP3R protein levels, impairing mitochondrial calcium uptake and oxidative phosphorylation, and activating CHOP while suppressing PGC-1α-mediated mitochondrial biogenesis.\",\n      \"method\": \"Co-immunoprecipitation (DDRGK1-IP3R), ubiquitination assays, respirometry, ATP measurements, calcium uptake assays, CHOP/PGC-1α pathway analysis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding by Co-IP and ubiquitination protection assay, multiple bioenergetic readouts, single lab, abstract only\",\n      \"pmids\": [\"42171880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Depletion of DDRGK1 (along with UFL1 and UFM1) in human macrophages results in increased IFN-β production and secretion during Mycobacterium marinum and M. tuberculosis infection, indicating that UFMylation activity (including DDRGK1) is required to suppress Type I IFN signaling during mycobacterial infection.\",\n      \"method\": \"Genome-wide CRISPRi screen in human macrophages, siRNA depletion of DDRGK1, IFN-β ELISA, transcriptional profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CRISPRi screen hit with siRNA validation, single functional readout, preprint not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DDRGK1 (UFBP1) is an ER-localized adaptor protein and core component of the UFM1 conjugation system that stabilizes multiple client proteins—including IRE1α, SOX9, NRF2/FASN, IP3R, and IκBα—by protecting them from ubiquitin-proteasomal degradation, thereby maintaining ER homeostasis (via IRE1α-XBP1 signaling), regulating chondrogenesis, hematopoiesis, and plasma cell development; its own stability and functions are modulated by ufmylation (primarily at K267/K268), and it functions within a UFL1/UFBP1 complex that also attenuates mTORC1 activity and suppresses Type I IFN signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDRGK1 (UFBP1) is an endoplasmic reticulum membrane protein that serves as a core component and substrate adaptor of the UFM1 conjugation (ufmylation) system, governing ER homeostasis and the stability of multiple client proteins [#0, #3]. Within a UFL1/UFBP1 complex it both transfers UFM1 and is itself ufmylated, and its own stability is maintained by UFL1, which protects it from proteasomal degradation [#1]. A recurrent theme across its targets is control of client protein turnover: DDRGK1 stabilizes the ER-stress sensor IRE1\\u03b1 by binding its kinase domain in a ufmylation-dependent manner, sustaining IRE1\\u03b1-XBP1 signaling and suppressing the PERK-eIF2\\u03b1-CHOP apoptotic arm [#3, #12]. The same protective logic extends to the chondrogenic master regulator SOX9, whose ubiquitination DDRGK1 blocks to drive cartilage development [#4], and to FASN and IP3R, which DDRGK1 stabilizes by competitively inhibiting their ubiquitination [#19, #20]. Through these activities DDRGK1 controls embryonic development and hematopoiesis, where its loss elevates ER stress and represses erythroid transcription factors via ASC1-dependent promoter association [#5], and promotes plasma cell development by restraining PERK [#6]. Site-specific ufmylation of DDRGK1 (K267/K268) is required for several functions including IRE1\\u03b1 stabilization, control of hepatic lipogenesis, and FASN-dependent adiposity [#12, #15, #19], though this modification is dispensable for embryonic, cardiac, and intestinal homeostasis [#16]. The UFL1/UFBP1 complex additionally attenuates mTORC1 by directly engaging the mTOR/G\\u03b2L complex [#11], and DDRGK1 modulates autophagy and ER-phagy [#10, #14]. Reported effects on NRF2 stability are conflicting, with evidence for both promoting [#8] and inhibiting [#9] its degradation.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established DDRGK1 as a stable member of a UFL1 (RCAD)/CDK5RAP3 (C53/LZAP) protein complex and showed its abundance is set by UFL1-dependent protection from proteasomal degradation, defining the molecular context for its later adaptor roles.\",\n      \"evidence\": \"Co-IP, gel filtration, and ubiquitination assays with proteasome inhibition\",\n      \"pmids\": [\"20228063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the E3 ligase responsible for DDRGK1 ubiquitination\", \"Did not connect complex assembly to ufmylation enzymology\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed DDRGK1 at the ER as a UFM1-conjugation partner required to prevent ER-stress-induced apoptosis, linking the ufmylation machinery (UFM1, UFL1, UFBP1) to ER homeostasis.\",\n      \"evidence\": \"Immunofluorescence co-localization, reciprocal Co-IP, and siRNA knockdown with apoptosis readout in pancreatic beta cells\",\n      \"pmids\": [\"21494687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular target of the protective effect identified\", \"Mechanism connecting ufmylation to apoptosis suppression unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Proposed DDRGK1 regulates NF-\\u03baB signaling by controlling I\\u03baB\\u03b1 stability, extending its client-stabilization role to inflammatory transcription.\",\n      \"evidence\": \"Co-IP, NF-\\u03baB target microarray, and siRNA knockdown with proliferation/invasion assays\",\n      \"pmids\": [\"23675531\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation for I\\u03baB\\u03b1 binding\", \"Direction and mechanism of stability control not biochemically dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated DDRGK1 is essential for embryonic development and hematopoiesis in vivo, tying ER-stress control to stem/progenitor survival and erythroid transcription factor expression.\",\n      \"evidence\": \"Germline and conditional KO mice, ChIP for ASC1 at GATA-1/KLF1 promoters, siRNA in K562 cells\",\n      \"pmids\": [\"26544067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How UFBP1 controls ASC1 promoter recruitment mechanistically unclear\", \"Direct versus indirect regulation of GATA-1/KLF1 not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the key mechanistic principle that DDRGK1 stabilizes IRE1\\u03b1 by binding its kinase domain in a ufmylation-dependent manner, balancing the IRE1\\u03b1-XBP1 versus PERK-CHOP arms of the UPR.\",\n      \"evidence\": \"Domain-mapped Co-IP, siRNA knockdown, ufmylation mutant analysis, UPR pathway readouts\",\n      \"pmids\": [\"28128204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase degrading IRE1\\u03b1 in DDRGK1's absence not identified\", \"Structural basis of kinase-domain recognition unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed DDRGK1 directly binds and protects SOX9 from ubiquitination, establishing a developmental client and a genetic role in chondrogenesis confirmed by rescue.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, zebrafish knockdown with sox9 rescue, Ddrgk1-/- mouse with SOX9/Col2a1 readouts\",\n      \"pmids\": [\"28263186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SOX9 protection requires DDRGK1 ufmylation not established here\", \"E3 ligase acting on SOX9 not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reframed DDRGK1 as a broad interactome hub that, contrary to its IRE1\\u03b1/SOX9 stabilizing role, can promote client ubiquitination by enhancing substrate-E3 ligase engagement.\",\n      \"evidence\": \"IP-MS interactome (~80 proteins), ubiquitination assays using ANT3 as model substrate\",\n      \"pmids\": [\"29533670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What determines whether DDRGK1 stabilizes versus degrades a client unresolved\", \"Which E3 ligases are recruited not systematically mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified UFBP1 ufmylation at K267 as functionally required for immunoglobulin production and ER expansion in plasma cells, while showing it promotes plasma cell development by suppressing PERK in a feedback loop with IRE1\\u03b1/XBP1.\",\n      \"evidence\": \"Conditional KO mice, K267R mutant, plasma cell differentiation and immunoglobulin assays\",\n      \"pmids\": [\"30842412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of K267 ufmylation in ER expansion not defined\", \"Distinction between K267 ufmylation-dependent and -independent functions partial\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported UFBP1 promotes K48-linked ubiquitination and degradation of NRF2, suppressing antioxidant gene expression and sensitizing gastric cancer cells to cisplatin.\",\n      \"evidence\": \"SILAC proteomics, K48-linkage ubiquitination assay, knockdown/overexpression, ROS flow cytometry, xenografts\",\n      \"pmids\": [\"33219317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directly contradicts later report of NRF2 stabilization (idx 9)\", \"E3 ligase mediating NRF2 degradation not specified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a dual, opposing role of DDRGK1 in autophagy: it restrains mTOR to permit autophagy induction while being required for autophagosome-lysosome fusion and lysosomal function.\",\n      \"evidence\": \"Inducible conditional KO MEFs, autophagy flux and mTOR assays, lysosomal pH, Cathepsin D, v-ATPase analysis\",\n      \"pmids\": [\"33879777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between DDRGK1 and lysosomal acidification machinery unknown\", \"Whether mTOR and fusion effects are mechanistically connected unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Proposed DDRGK1 binds Smad3 and suppresses its phosphorylation, limiting hepatic fibrosis through a TGF-\\u03b2/Smad-restraining role distinct from its degradation functions.\",\n      \"evidence\": \"Endogenous Co-IP, conditional KO mice, overexpression, phospho-Smad2/3 analysis\",\n      \"pmids\": [\"34307359\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single endogenous Co-IP without reciprocal validation\", \"Mechanism of selective Smad3 (not Smad2) phospho-suppression unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed in vivo, with K268R knockin mice, that DDRGK1 ufmylation drives IRE1\\u03b1 ufmylation and protection from ubiquitin-mediated degradation in chondrocytes, validating the modification's physiological importance.\",\n      \"evidence\": \"Conditional KO and K268R knockin mice, UFMylation/ubiquitylation competitive assays, PERK/CHOP/Caspase3 analysis\",\n      \"pmids\": [\"37781516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How IRE1\\u03b1 ufmylation status determines its ubiquitination not biochemically resolved\", \"Tissue-specificity of K268 requirement unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed the UFL1/UFBP1 complex directly binds the mTOR/G\\u03b2L complex to attenuate mTORC1 activity, with loss driving hepatocellular carcinoma, providing a direct molecular basis for the earlier mTOR/autophagy phenotype.\",\n      \"evidence\": \"Co-IP of the complex, hepatocyte conditional KO mice, iTRAQ proteomics, HCC tumor models\",\n      \"pmids\": [\"37131258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mTOR attenuation requires ufmylation activity unclear\", \"Direct site of mTOR/G\\u03b2L engagement not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reported the opposite of the 2020 NRF2 finding: DDRGK1 competitively binds KEAP1 to stabilize NRF2 and promote antioxidant responses, modulating chemosensitivity in osteosarcoma.\",\n      \"evidence\": \"Quantitative proteomics, competitive Co-IP, DDRGK1 KO, ROS measurement, xenografts\",\n      \"pmids\": [\"36965071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directly contradicts idx 8 on the direction of NRF2 regulation\", \"Context dependence (cancer type) of the opposing effects unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that UFBP1 ufmylation at K267 alleviates ER-stress-driven hepatic lipogenesis, linking the modification to metabolic disease phenotypes via rescue with WT but not K267R protein.\",\n      \"evidence\": \"K267R rescue in vitro, HFD mouse model with WT vs K267R UFBP1, ER stress and lipid assays\",\n      \"pmids\": [\"37660122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipogenic effector downstream of K267 ufmylation not identified\", \"Relationship to IRE1\\u03b1/XBP1 axis in liver not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that UFBP1 K268 ufmylation is dispensable for ER stress signaling, embryonic, cardiac, and intestinal homeostasis, sharpening the boundaries of where the modification is functionally required.\",\n      \"evidence\": \"K268R knockin mice, MEF ER stress assays, echocardiography, DSS colitis model\",\n      \"pmids\": [\"37566002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why K268 ufmylation matters in some tissues (chondrocytes, adipose) but not others unresolved\", \"Compensatory ufmylation sites not excluded\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed DDRGK1-UFL1-mediated ER-phagy as a protective mechanism that mitigates ER stress and apoptosis in renal tubular cells.\",\n      \"evidence\": \"DDRGK1 overexpression in HK-2 cells, murine AKI models, ER-phagy flux assays\",\n      \"pmids\": [\"38233375\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic dissection of ER-phagy receptor function\", \"Causal role of DDRGK1 versus correlation not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated DDRGK1 and the UFMylation machinery in suppressing Type I IFN during mycobacterial infection in macrophages.\",\n      \"evidence\": \"Genome-wide CRISPRi screen with siRNA validation, IFN-\\u03b2 ELISA, transcriptional profiling (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Single functional readout; molecular target of IFN suppression not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended DDRGK1's client-stabilization role to FASN, IP3R, and to upstream regulation by XIAP, connecting ufmylation to lipogenesis/adiposity, mitochondrial calcium/bioenergetics, and ER-phagy-mediated cochlear protection.\",\n      \"evidence\": \"K268R knockin mice with HFD and FASN ubiquitination assay; Co-IP and ubiquitination assays for IP3R; XIAP-DDRGK1 Co-IP with ER-phagy and noise-exposure models\",\n      \"pmids\": [\"41671397\", \"42171880\", \"41588674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IP3R and XIAP findings are abstract/single-Co-IP level (Low confidence)\", \"E3 ligases acting on FASN and IP3R not identified\", \"Whether these stabilizations require DDRGK1 ufmylation not uniformly tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular feature determines whether DDRGK1 stabilizes a client (IRE1\\u03b1, SOX9, FASN, IP3R) versus promotes its degradation (ANT3, NRF2 per idx 8), and the contradictory directionality of NRF2 regulation is unexplained.\",\n      \"evidence\": \"No timeline study reconciles the bidirectional adaptor behavior or the conflicting NRF2 results\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying biochemical model for substrate fate selection\", \"E3 ligase recruitment specificity uncharacterized\", \"Structural basis of client recognition unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 7, 19]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 4, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005789\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"UFL1/UFBP1 (UFM1 E3 ligase) complex\",\n      \"UFL1/UFBP1/CDK5RAP3 (C53/LZAP) complex\"\n    ],\n    \"partners\": [\n      \"UFL1\",\n      \"UFM1\",\n      \"CDK5RAP3\",\n      \"ERN1 (IRE1\\u03b1)\",\n      \"SOX9\",\n      \"KEAP1\",\n      \"MTOR\",\n      \"FASN\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}