{"gene":"IFRD1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2002,"finding":"TIS7 (IFRD1) is a novel transcriptional co-repressor that associates with the mammalian SIN3 histone deacetylase complex, interacting with mSin3B, HDAC1, N-CoR, and SAP30 as demonstrated by yeast two-hybrid screening and co-immunoprecipitation. The TIS7-co-immunoprecipitated HDAC complex is enzymatically active and represses GAL4-dependent reporter transcription. TIS7 nuclear localization correlates with loss of cell polarity in mammary epithelial cells.","method":"Yeast two-hybrid screening, co-immunoprecipitation, HDAC enzymatic activity assay, cDNA microarray, immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP with enzymatic activity validation, multiple orthogonal methods (Y2H, Co-IP, reporter assay, microarray), single lab","pmids":["12198164"],"is_preprint":false},{"year":2009,"finding":"IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Ifrd1-deficient mouse neutrophils (but not macrophages) show blunted effector function associated with decreased NF-κB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway but reduced inflammation, a phenotype dependent on haematopoietic cell expression of IFRD1.","method":"Ifrd1 knockout mice, bone marrow transplantation (haematopoietic reconstitution), NF-κB reporter assay, neutrophil functional assays, in vivo airway infection model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, haematopoietic rescue experiment, NF-κB mechanistic assay, replicated in human polymorphism data","pmids":["19242412"],"is_preprint":false},{"year":2005,"finding":"TIS7 (IFRD1) down-regulates beta-catenin/Tcf-4 transcriptional activity and the expression of downstream target genes (c-Myc, osteopontin/OPN) in a histone deacetylase-dependent manner. TIS7 overexpression leads to beta-catenin interaction with enzymatically active histone deacetylases. TIS7 homologous deletion in mouse embryonic fibroblasts increased TOPflash reporter activity, c-Myc, and OPN expression.","method":"TOPflash reporter assay, co-immunoprecipitation, HDAC activity assay, TIS7 knockout mouse embryonic fibroblasts, qRT-PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay, Co-IP with HDAC activity, KO fibroblast validation, single lab with multiple methods","pmids":["16204248"],"is_preprint":false},{"year":2004,"finding":"TIS7 (IFRD1) inhibits C/EBPalpha-Sp1 transcription factor module activity by specifically interfering with Sp1 transcriptional activity and preventing formation of a complex between Sp1 protein and its consensus DNA binding site, as identified by bioinformatic analysis of TIS7-regulated gene promoters and confirmed by reporter assays and electrophoretic mobility shift assay (EMSA).","method":"Bioinformatic promoter analysis, reporter assay, EMSA (Sp1-DNA binding assay)","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reporter assay and EMSA in single lab, two orthogonal methods","pmids":["15095974"],"is_preprint":false},{"year":2004,"finding":"TIS7 (IFRD1) knockout mice display delayed injury-induced muscle regeneration and altered isometric contractile properties after crush damage. Primary myogenic satellite cells from TIS7(-/-) mice show reduced differentiation potential and fusion index in a cell-autonomous fashion, with down-regulation of MyoD, myogenin, and laminin-alpha2. Fusion potential could be rescued by TIS7 re-expression or laminin supplementation.","method":"Tis7 knockout mice (homologous recombination), muscle crush injury model, primary satellite cell culture, rescue experiment (TIS7 re-expression, laminin supplementation), immunostaining","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular and organismal phenotype, cell-autonomous rescue experiment, multiple orthogonal readouts","pmids":["15060170"],"is_preprint":false},{"year":2010,"finding":"PC4/TIS7 (IFRD1) functions as a negative regulator of NF-κB in myoblasts: PC4 up-regulation induces deacetylation and nuclear export of NF-κB p65, while PC4 silencing induces p65 acetylation and nuclear import, with corresponding changes in MyoD expression. PC4 forms trimolecular complexes with p65 and HDAC3, suggesting it recruits HDAC3 to deacetylate p65. PC4 potentiates inhibition of NF-κB transcriptional activity mediated by histone deacetylases.","method":"PC4 overexpression/siRNA silencing in primary myoblasts, NF-κB reporter assay, co-immunoprecipitation (trimolecular complex), nuclear fractionation, immunostaining, in vivo muscle overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of trimolecular complex, nuclear fractionation, reporter assay, KD and OE with complementary phenotypes, single lab multiple methods","pmids":["21127072"],"is_preprint":false},{"year":1994,"finding":"The TIS7/PC4 protein is a membrane-associated, non-nuclear intracellular protein (as opposed to TIS21/PC3 which is a non-nuclear soluble protein), as determined by immunohistochemistry and subcellular fractionation. Pulse-chase experiments demonstrate TIS7/PC4 protein is degraded more slowly than TIS21/PC3. Secretion of TIS7/PC4 protein could not be detected.","method":"Immunohistochemistry, subcellular fractionation, pulse-chase radiolabeling, immunoprecipitation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation and immunostaining with functional context, single lab, two orthogonal methods","pmids":["8263025"],"is_preprint":false},{"year":2010,"finding":"IFRD1 mRNA stability is regulated post-transcriptionally by an upstream open reading frame (uORF): translation of the uORF in resting cells promotes instability of the major ORF mRNA. During cellular stress (ER stress via tunicamycin), eIF2alpha phosphorylation inhibits translational initiation, stabilizing the IFRD1 mRNA and elevating IFRD1 protein. The instability mechanism depends on UPF1 (nonsense-mediated decay pathway), and is determined by uORF sequence and length but not by a specific encoded peptide.","method":"Tunicamycin treatment, mRNA stability assay, reporter constructs with uORF mutations, eIF2alpha phosphorylation analysis, UPF1 knockdown, polysome profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple uORF mutant constructs, UPF1 KD, polysome analysis, mechanistically detailed single lab study","pmids":["20080976"],"is_preprint":false},{"year":2016,"finding":"Ifrd1 (IFRD1) regulates osteoclast differentiation through the NF-κB/NFATc1 pathway: Ifrd1 deficiency increases acetylation of p65 at residues K122 and K123 via inhibition of histone deacetylase-dependent deacetylation in bone marrow macrophages, thereby repressing NF-κB-dependent transcription of NFATc1. Global Ifrd1 deletion in mice increased bone mass by decreasing bone resorption. Ifrd1 expression in preosteoclasts is transcriptionally regulated by RANKL through activator protein 1.","method":"Ifrd1 knockout mice, bone marrow macrophage osteoclastogenesis assay, p65 acetylation analysis (site-specific K122/K123), HDAC inhibitor treatment, NFATc1 reporter assay, microCT bone analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with bone phenotype, site-specific acetylation mapping, HDAC-dependence shown, reporter assay, multiple methods single lab","pmids":["27381458"],"is_preprint":false},{"year":2013,"finding":"TIS7 (IFRD1) inhibits adipogenesis by promoting Wnt/β-catenin signaling: TIS7 overexpression in 3T3-L1 cells inhibits adipogenic gene expression, and this effect requires Wnt/β-catenin activity (abolished by dominant-negative TCF4). Under hypoxia, TIS7 predominantly interacts with β-catenin in the nucleus of adipose tissue. TIS7 expression is induced by hypoxia via ATF6-dependent transcriptional activation of the TIS7 promoter.","method":"TIS7 overexpression/shRNA knockdown in 3T3-L1 cells, co-immunoprecipitation (TIS7–β-catenin), reporter assay, dominant-negative TCF4, ATF6 shRNA knockdown, Oil Red O staining, in vivo ob/ob mouse model","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, DN rescue, ATF6 KD, multiple readouts, single lab","pmids":["23517917"],"is_preprint":false},{"year":2016,"finding":"TIS7 (IFRD1) directly binds DNA and controls a transcriptional cascade involving ICln and PRMT5. TIS7/ICln epigenetically regulate MyoD expression via symmetrical di-methylation of histone H3 on arginine 8 through PRMT5 activity, thereby controlling skeletal muscle differentiation.","method":"ChIP (direct DNA binding), co-immunoprecipitation (TIS7-ICln-PRMT5), histone methylation assay (H3R8me2s), MyoD expression analysis, myoblast differentiation assay","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct DNA binding, Co-IP, histone modification assay, single lab with multiple methods","pmids":["27782840"],"is_preprint":false},{"year":2017,"finding":"Ifrd1 (IFRD1) negatively regulates thermogenic and mitochondrial gene expression (including PGC-1α/Pgc1a) in brown adipocytes by forming a complex with Sp1 and mSIN3B (a component of the histone deacetylase-containing SIN complex) upon adrenergic stimulation. Ifrd1 represses Sp1-mediated Pgc1a promoter activity in an HDAC-dependent manner (reversed by trichostatin A). Adrenergic stimulation induces Ifrd1 expression through CREB-dependent transcription.","method":"Ifrd1 knockout mice, co-immunoprecipitation (Ifrd1-Sp1-mSIN3B complex), Pgc1a promoter-reporter assay, trichostatin A treatment, CL-316243 in vivo administration, CREB analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of trimolecular complex, HDAC-dependence via TSA, KO mouse, reporter assay, single lab","pmids":["28107769"],"is_preprint":false},{"year":2018,"finding":"Ifrd1 (IFRD1) is a transcriptional corepressor that suppresses p65 nuclear translocation; its proteasomal degradation (induced by oridonin treatment) abolishes this suppression and allows p65 nuclear entry. Ifrd1 deficiency in osteoclast precursors increases p65 K122/K123 acetylation via HDAC inhibition, blunting NF-κB signaling. Oridonin-induced Ifrd1 degradation also promotes Smad1/Smad5 phosphorylation and osteoblast differentiation.","method":"Proteasomal degradation assay, p65 nuclear localization immunofluorescence, Ifrd1 KO osteoclast precursors, IκBα phosphorylation assay, Smad1/5 phosphorylation assay, ovariectomy mouse model","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteasomal degradation shown, nuclear localization assay, p65 acetylation, KO model, single lab","pmids":["29091322"],"is_preprint":false},{"year":2024,"finding":"IFRD1 promotes adaptive survival of hepatocellular carcinoma cells under glutamine starvation by inhibiting autophagy via promoting proteasomal degradation of the autophagy regulator ATG14 in a TRIM21-dependent manner. IFRD1 depletion under glutamine starvation increases autophagy flux, leading to nucleophagic degradation of histone H1.0, unchecked ribosome/protein biosynthesis, and cancer cell death. IFRD1 and TRIM21 interact (shown by co-IP), and IFRD1 prevents ATG14 from sustaining autophagy.","method":"IFRD1 knockdown/overexpression in HCC cells, glutamine starvation, co-immunoprecipitation (IFRD1-TRIM21), ATG14 proteasomal degradation assay, autophagy flux assay, nucleophagy (histone H1.0 degradation) assay, preclinical HCC models with CB-839","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, proteasomal degradation, autophagy flux, multiple cell and in vivo models, single lab","pmids":["38802351"],"is_preprint":false},{"year":2024,"finding":"IFRD1 interacts with mRNA-translation-regulating factors in human urothelial cells. Loss of Ifrd1 in mouse bladder leads to disrupted proteostasis, enhanced ER stress with activation of the PERK arm of the unfolded protein response, increased oxidative stress, urothelial cell apoptosis/exfoliation, enhanced basal cell proliferation, reduced differentiation into superficial cells, increased urothelial permeability, and aberrant voiding behavior.","method":"Ifrd1 knockout mice, co-immunoprecipitation (IFRD1 with translation factors), transcriptome analysis (RNA-seq), electron microscopy (organelle accumulation), UPR/PERK pathway analysis, voiding behavior assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype, Co-IP for interaction, pathway analysis, multiple readouts, single lab","pmids":["39628564"],"is_preprint":false},{"year":2023,"finding":"Ifrd1 (IFRD1) controls Wnt signaling and thereby transcriptionally regulates Dlk1 (a negative regulator of adipogenesis), while its paralogue Ifrd2 acts as a translational inhibitor of Dlk1 protein levels. Double knockout (dKO) mice lacking both Ifrd1 and Ifrd2 have severely reduced adipose tissue, resistance to high-fat diet-induced obesity, upregulated Wnt/β-catenin signaling, elevated Dlk1, and reduced Pparg, Cebpa, and Cd36 expression.","method":"Ifrd1/Ifrd2 double knockout mice, Wnt/β-catenin pathway analysis, Dlk1 transcription and translation assays, high-fat diet feeding, adipose tissue histology, qRT-PCR, immunoblot","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double KO mouse with defined phenotype, separate transcriptional (Ifrd1) vs translational (Ifrd2) mechanism dissected, single lab","pmids":["37603466"],"is_preprint":false},{"year":2026,"finding":"IFRD1 stabilizes SLC25A5 (mitochondrial ADP/ATP translocator) by competing with the E3 ubiquitin ligase TRIM21, thereby sustaining hepatocyte β-oxidation and mitochondrial ATP production. This ATP boost enables chromatin remodeling that promotes CCL/CXC chemokine expression, recruiting CCR2+ monocytes and expanding the regenerative GPNMB+ macrophage pool to facilitate liver regeneration. Hepatocyte-specific IFRD1 loss impairs liver repair while IFRD1 overexpression enhances regeneration across multiple models.","method":"Hepatocyte-specific IFRD1 KO and AAV-mediated overexpression, Co-IP (IFRD1-SLC25A5-TRIM21), mitochondrial ATP production assay, β-oxidation assay, ATAC-seq, single-nucleus RNA-seq, partial hepatectomy and toxic liver injury models","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO, Co-IP protein interactions, metabolic assays, chromatin assay, single lab with multiple orthogonal methods","pmids":["41861961"],"is_preprint":false},{"year":2026,"finding":"IFRD1 is primarily a cytosolic ribosome-binding protein that specifically binds 80S monosomes not actively engaged in translation. During ER stress (tunicamycin) and in vivo injury (cerulein-induced pancreatitis), IFRD1 acts as a ribosome-salvaging factor preventing ribosomes from disassembly and selective degradation. In IFRD1-deficient cells, non-translating 80S ribosomes are unstable, degrade, accumulate as p62-tagged cargo overwhelming autophagy, reduce mTORC1 activity, and increase cell death.","method":"Polysome/ribosome fractionation, IFRD1 KO cells and mice, cerulein pancreatitis model, tunicamycin ER stress model, p62 autophagy assay, mTORC1 activity assay, ribosome stability assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome fractionation, multiple in vivo and in vitro models, mTORC1 readout, single lab preprint not yet peer-reviewed","pmids":["42146531"],"is_preprint":true},{"year":2026,"finding":"IFRD1 promotes GLUD1 mitochondrial localization via direct protein-protein interaction, stabilizing GLUD1 enzyme activity to enhance α-ketoglutarate (α-KG) production. Elevated α-KG reduces H3K36me3 levels at lipogenic gene loci, inhibiting de novo lipogenesis and ameliorating metabolic steatohepatitis (MASH). Ifrd1 knockout mice exhibit exacerbated MASLD; α-KG supplementation reverses this phenotype.","method":"Co-immunoprecipitation (IFRD1-GLUD1), GLUD1 enzymatic activity assay, mitochondrial fractionation, α-KG metabolite measurement, H3K36me3 ChIP-seq at lipogenic genes, Ifrd1 conditional KO mice, MASLD mouse models, α-KG rescue experiment","journal":"Science bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction by Co-IP, enzyme activity assay, ChIP-seq for histone marks, KO with rescue, multiple methods single lab","pmids":["41997855"],"is_preprint":false},{"year":2016,"finding":"BMP-2 directly induces Ifrd1 expression at the transcriptional level in osteoblasts via the Smad pathway: BMP-2 stimulation induces recruitment of Smad1 to the Ifrd1 promoter (which contains conserved Smad-binding elements), and co-introduction of Smad1 and Smad4 increases Ifrd1 promoter activity. Ifrd1 knockdown in osteoblasts enhanced BMP-2-dependent osteoblastogenesis, indicating Ifrd1 negatively feeds back on this process.","method":"ChIP (Smad1 recruitment to Ifrd1 promoter), Ifrd1 promoter-reporter assay, Smad1/4 co-transfection, LDN193189 inhibitor, Ifrd1 siRNA knockdown, Alizarin Red staining, marker gene qRT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and promoter reporter assay, KD with functional readout, single lab","pmids":["27856249"],"is_preprint":false},{"year":2024,"finding":"MTHFD2 increases m6A methylation of IFRD1 RNA, which upregulates IFRD1 protein expression and activates the HDAC3/p53/mTOR pathway, promoting breast cancer cell proliferation. IFRD1 siRNA transfection reversed the proliferative effects of MTHFD2 overexpression, placing IFRD1 downstream of MTHFD2-mediated m6A modification.","method":"MTHFD2 overexpression/knockdown, m6A methylation assay on IFRD1 mRNA, IFRD1 siRNA rescue, cell proliferation assay (EdU), cell cycle analysis, HDAC3/p53/mTOR pathway western blot","journal":"Neoplasma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, m6A assay and rescue experiment but limited mechanistic depth on IFRD1's direct action","pmids":["39832202"],"is_preprint":false}],"current_model":"IFRD1/TIS7 is a stress-responsive, histone-deacetylase-dependent transcriptional co-regulator that assembles with the SIN3–HDAC complex (via mSin3B, HDAC1/3, N-CoR, SAP30) to repress specific gene sets; it modulates NF-κB p65 transactivation by recruiting HDAC3 to promote p65 deacetylation and nuclear export, controls skeletal muscle differentiation via MyoD (through an ICln/PRMT5-H3R8me2s epigenetic axis and NF-κB suppression), inhibits Wnt/β-catenin target genes and adipogenesis, regulates osteoclastogenesis through an Ifrd1/NF-κB/NFATc1 axis, stabilizes mitochondrial SLC25A5 (competing with TRIM21 ubiquitin ligase) to sustain ATP production and chromatin remodeling in hepatocytes, promotes GLUD1 mitochondrial localization to enhance α-KG production and suppress lipogenic gene chromatin marks, and in the cytosol binds non-translating 80S ribosomes to protect them from stress-induced disassembly and degradation, thereby preserving mTORC1 activity and cell survival during metabolic transitions."},"narrative":{"mechanistic_narrative":"IFRD1 (TIS7/PC4) is a stress-responsive, histone-deacetylase-dependent transcriptional co-regulator that couples cellular stress signals to repression of defined gene programs across differentiation, immunity, and metabolism [PMID:12198164, PMID:19242412]. It assembles with the mammalian SIN3–HDAC complex, interacting with mSin3B, HDAC1, N-CoR, and SAP30 to deliver enzymatically active deacetylase activity to target promoters [PMID:12198164]. A recurring mechanistic theme is its control of NF-κB: IFRD1 forms trimolecular complexes with p65 and HDAC3, driving p65 deacetylation and nuclear export, and its loss elevates p65 K122/K123 acetylation, thereby tuning NF-κB-dependent transcription in neutrophils, myoblasts, and osteoclast precursors [PMID:19242412, PMID:21127072, PMID:27381458]. Through HDAC-dependent and direct DNA-binding routes it represses Wnt/β-catenin–TCF target genes (c-Myc, osteopontin) and Sp1-driven programs [PMID:16204248, PMID:15095974, PMID:27782840, PMID:28107769]. These activities position IFRD1 as a controller of skeletal muscle regeneration via MyoD, acting partly through an ICln/PRMT5 H3R8me2s epigenetic axis [PMID:15060170, PMID:27782840], of osteoclast differentiation via an NF-κB/NFATc1 axis [PMID:27381458], and of adipogenesis and thermogenic gene expression [PMID:23517917, PMID:28107769, PMID:37603466]. IFRD1 expression is itself stress-gated: an upstream ORF destabilizes its mRNA via UPF1-dependent decay in resting cells, while eIF2α phosphorylation during ER stress stabilizes the transcript and elevates protein [PMID:20080976]. Beyond transcription, IFRD1 has cytoplasmic functions, stabilizing the mitochondrial proteins SLC25A5 and GLUD1 by competing with the TRIM21 ubiquitin ligase to sustain ATP production, β-oxidation, and α-ketoglutarate–dependent chromatin remodeling in hepatocytes [PMID:41861961, PMID:41997855], and acting as a cytosolic ribosome-salvaging factor that binds non-translating 80S monosomes to protect them from stress-induced degradation, preserving mTORC1 activity and survival [PMID:42146531].","teleology":[{"year":1994,"claim":"Established the basic cell biology of the TIS7/PC4 protein before any molecular activity was known, distinguishing it as a stable, membrane-associated intracellular protein.","evidence":"Immunohistochemistry, subcellular fractionation, and pulse-chase radiolabeling","pmids":["8263025"],"confidence":"Medium","gaps":["No molecular function assigned","Localization later refined to nuclear and cytosolic compartments by other studies"]},{"year":2002,"claim":"Answered what IFRD1 does molecularly by identifying it as a SIN3–HDAC-associated transcriptional co-repressor, defining its core mechanism of action.","evidence":"Yeast two-hybrid, reciprocal co-IP with HDAC enzymatic activity assay, and reporter assay in mammary epithelial cells","pmids":["12198164"],"confidence":"High","gaps":["Direct DNA binding not established at this stage","Specific endogenous target genes not defined"]},{"year":2004,"claim":"Connected IFRD1's co-repressor activity to a physiological program by showing it is required cell-autonomously for muscle differentiation and regeneration via MyoD/myogenin.","evidence":"Tis7 knockout mice, muscle crush injury, primary satellite cell culture with rescue","pmids":["15060170"],"confidence":"High","gaps":["Molecular link between co-repressor function and MyoD induction not yet defined","Laminin-alpha2 regulation mechanism unresolved"]},{"year":2004,"claim":"Identified Sp1 as a specific transcriptional target of IFRD1 interference, broadening its repertoire beyond generic HDAC recruitment.","evidence":"Bioinformatic promoter analysis, reporter assay, and EMSA","pmids":["15095974"],"confidence":"Medium","gaps":["Whether IFRD1 binds Sp1 directly versus blocking DNA occupancy indirectly not fully resolved","No in vivo validation"]},{"year":2005,"claim":"Showed IFRD1 represses Wnt/β-catenin–TCF target genes in an HDAC-dependent manner, defining a pathway-level repression target.","evidence":"TOPflash reporter, co-IP, HDAC activity assay, and TIS7 knockout MEFs","pmids":["16204248"],"confidence":"Medium","gaps":["Mechanism of β-catenin–HDAC bridging not structurally defined","Direct versus indirect recruitment unresolved"]},{"year":2009,"claim":"Demonstrated a physiological immune role, with IFRD1 required for neutrophil effector function through NF-κB p65 transactivation in vivo.","evidence":"Ifrd1 knockout mice, haematopoietic reconstitution, NF-κB reporter, airway infection model","pmids":["19242412"],"confidence":"High","gaps":["Direct molecular mechanism of p65 regulation not yet mapped","Neutrophil-specific target genes not enumerated"]},{"year":2010,"claim":"Defined the molecular mechanism of NF-κB regulation: IFRD1 recruits HDAC3 to p65, driving its deacetylation and nuclear export.","evidence":"Overexpression/silencing in myoblasts, co-IP of p65-HDAC3 trimolecular complex, nuclear fractionation","pmids":["21127072"],"confidence":"High","gaps":["Site-specific p65 residues deacetylated not yet mapped in this study","Stoichiometry of the complex unresolved"]},{"year":2010,"claim":"Explained how IFRD1 itself is stress-induced, identifying a uORF/UPF1-dependent decay mechanism relieved by eIF2α phosphorylation during ER stress.","evidence":"Tunicamycin treatment, uORF mutant reporters, UPF1 knockdown, polysome profiling, eIF2α phosphorylation analysis","pmids":["20080976"],"confidence":"High","gaps":["Whether stabilized protein localizes to specific compartments under stress not addressed","Link to downstream functional outputs not tested here"]},{"year":2013,"claim":"Extended IFRD1's Wnt control to metabolism, showing hypoxia/ATF6-induced IFRD1 promotes Wnt signaling to inhibit adipogenesis.","evidence":"3T3-L1 overexpression/knockdown, TIS7–β-catenin co-IP, dominant-negative TCF4, ATF6 knockdown, ob/ob model","pmids":["23517917"],"confidence":"Medium","gaps":["Apparent context-dependent activation versus repression of Wnt not reconciled","Direct β-catenin binding interface undefined"]},{"year":2016,"claim":"Resolved the muscle differentiation mechanism by showing IFRD1 binds DNA directly and uses an ICln/PRMT5 H3R8me2s axis to control MyoD.","evidence":"ChIP for direct DNA binding, co-IP of TIS7-ICln-PRMT5, H3R8me2s histone methylation assay","pmids":["27782840"],"confidence":"Medium","gaps":["DNA sequence specificity of IFRD1 binding not defined","How HDAC and PRMT5 activities are coordinated unclear"]},{"year":2016,"claim":"Mapped IFRD1's role in bone, defining an NF-κB/NFATc1 axis via site-specific p65 K122/K123 deacetylation controlling osteoclastogenesis.","evidence":"Ifrd1 knockout mice, bone marrow macrophage osteoclastogenesis, site-specific acetylation analysis, microCT","pmids":["27381458"],"confidence":"High","gaps":["Which HDAC executes K122/K123 deacetylation in this context not specified","Direct IFRD1 promoter targets in osteoclasts not enumerated"]},{"year":2016,"claim":"Placed IFRD1 in a negative feedback loop on osteoblast differentiation, induced transcriptionally by BMP-2/Smad signaling.","evidence":"ChIP of Smad1 at Ifrd1 promoter, promoter-reporter, Smad1/4 co-transfection, siRNA knockdown","pmids":["27856249"],"confidence":"Medium","gaps":["Downstream IFRD1 targets opposing osteoblastogenesis not identified","Interplay with osteoclast role in intact bone not integrated"]},{"year":2017,"claim":"Showed IFRD1 represses thermogenic and mitochondrial genes by forming an Sp1–mSIN3B complex on the Pgc1a promoter, linking it to brown fat function.","evidence":"Ifrd1 knockout mice, co-IP of Ifrd1-Sp1-mSIN3B, Pgc1a promoter-reporter, TSA treatment, CREB analysis","pmids":["28107769"],"confidence":"Medium","gaps":["Direct DNA contact versus Sp1-tethered recruitment at Pgc1a unresolved","Systemic energy expenditure consequences not fully quantified"]},{"year":2018,"claim":"Linked IFRD1 protein stability to function, showing proteasomal degradation relieves its suppression of p65 and shifts the osteoclast/osteoblast balance.","evidence":"Proteasomal degradation (oridonin) assay, p65 nuclear localization imaging, Ifrd1 KO precursors, Smad1/5 phosphorylation, ovariectomy model","pmids":["29091322"],"confidence":"Medium","gaps":["E3 ligase mediating IFRD1 degradation not identified here","Specificity of oridonin for IFRD1 not fully isolated"]},{"year":2023,"claim":"Dissected divergent IFRD1 versus IFRD2 mechanisms, with IFRD1 controlling Dlk1 transcriptionally via Wnt to restrain adipose development.","evidence":"Ifrd1/Ifrd2 double knockout mice, Wnt pathway analysis, Dlk1 transcription/translation assays, high-fat diet feeding","pmids":["37603466"],"confidence":"Medium","gaps":["Direct IFRD1 occupancy at the Dlk1 locus not shown","Functional redundancy boundaries between paralogues incompletely defined"]},{"year":2024,"claim":"Revealed a cytoplasmic, TRIM21-dependent function: IFRD1 promotes ATG14 degradation to restrain autophagy and enable HCC survival under glutamine starvation.","evidence":"IFRD1 knockdown/overexpression in HCC, IFRD1-TRIM21 co-IP, ATG14 degradation, autophagy/nucleophagy flux assays, CB-839 models","pmids":["38802351"],"confidence":"Medium","gaps":["How IFRD1 directs TRIM21 toward ATG14 mechanistically unclear","Relationship to nuclear co-repressor role not integrated"]},{"year":2024,"claim":"Connected IFRD1 to proteostasis and translation, showing its loss triggers PERK-arm UPR activation and urothelial differentiation/permeability defects.","evidence":"Ifrd1 knockout mice, co-IP with translation factors, RNA-seq, electron microscopy, UPR/PERK analysis, voiding assay","pmids":["39628564"],"confidence":"Medium","gaps":["Identity of the interacting translation factors not specified","Direct molecular role in translation versus transcription not separated"]},{"year":2024,"claim":"Placed IFRD1 downstream of MTHFD2-driven m6A modification feeding an HDAC3/p53/mTOR proliferative axis in breast cancer.","evidence":"MTHFD2 overexpression/knockdown, m6A assay on IFRD1 mRNA, IFRD1 siRNA rescue, proliferation and pathway analysis","pmids":["39832202"],"confidence":"Low","gaps":["Limited mechanistic depth on IFRD1's direct action in this axis","Single lab, not independently confirmed"]},{"year":2026,"claim":"Defined a mitochondrial metabolic function: IFRD1 stabilizes SLC25A5 by competing with TRIM21 to sustain ATP and chromatin remodeling supporting liver regeneration.","evidence":"Hepatocyte-specific KO and AAV overexpression, IFRD1-SLC25A5-TRIM21 co-IP, ATP/β-oxidation assays, ATAC-seq, snRNA-seq, hepatectomy models","pmids":["41861961"],"confidence":"Medium","gaps":["Structural basis of competition with TRIM21 unresolved","Generality of metabolic stabilization across tissues untested"]},{"year":2026,"claim":"Showed IFRD1 promotes GLUD1 mitochondrial localization to raise α-KG and lower H3K36me3 at lipogenic genes, ameliorating steatohepatitis.","evidence":"IFRD1-GLUD1 co-IP, GLUD1 activity assay, α-KG measurement, H3K36me3 ChIP-seq, conditional KO with α-KG rescue","pmids":["41997855"],"confidence":"Medium","gaps":["Direct interaction interface with GLUD1 not mapped","Whether α-KG effect is solely via histone demethylation unresolved"]},{"year":2026,"claim":"Established a translation-protective role: cytosolic IFRD1 binds non-translating 80S ribosomes to salvage them from stress-induced degradation, preserving mTORC1 and survival.","evidence":"Polysome/ribosome fractionation, IFRD1 KO cells and mice, cerulein and tunicamycin stress models, p62 and mTORC1 assays (preprint)","pmids":["42146531"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Structural basis of 80S monosome recognition undefined","Reconciliation of cytosolic ribosome role with nuclear co-repressor role open"]},{"year":null,"claim":"How IFRD1's distinct nuclear (SIN3-HDAC co-repressor), mitochondrial (SLC25A5/GLUD1 stabilization), and cytosolic (ribosome salvage) activities are partitioned and coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of IFRD1 domains assigned to each function","Signals dictating compartment-specific deployment unknown","Whether TRIM21 competition is a unifying mechanism across substrates untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator 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May be an autocrine factor that attenuates or amplifies the initial ligand-induced signal (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O00458/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFRD1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFRD1","total_profiled":1310},"omim":[{"mim_id":"607458","title":"SPINOCEREBELLAR ATAXIA 18; SCA18","url":"https://www.omim.org/entry/607458"},{"mim_id":"603502","title":"INTERFERON-RELATED DEVELOPMENTAL REGULATOR 1; IFRD1","url":"https://www.omim.org/entry/603502"},{"mim_id":"300907","title":"CLEAVAGE STIMULATION FACTOR, 3-PRIME PRE-RNA, SUBUNIT 2, 64-KD; 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Yi xue ban = Journal of Sichuan University. Medical science edition","url":"https://pubmed.ncbi.nlm.nih.gov/24527581","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23904,"output_tokens":6630,"usd":0.085581,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15664,"output_tokens":6450,"usd":0.119785,"stage2_stop_reason":"end_turn"},"total_usd":0.205366,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"TIS7 (IFRD1) is a novel transcriptional co-repressor that associates with the mammalian SIN3 histone deacetylase complex, interacting with mSin3B, HDAC1, N-CoR, and SAP30 as demonstrated by yeast two-hybrid screening and co-immunoprecipitation. The TIS7-co-immunoprecipitated HDAC complex is enzymatically active and represses GAL4-dependent reporter transcription. TIS7 nuclear localization correlates with loss of cell polarity in mammary epithelial cells.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, HDAC enzymatic activity assay, cDNA microarray, immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP with enzymatic activity validation, multiple orthogonal methods (Y2H, Co-IP, reporter assay, microarray), single lab\",\n      \"pmids\": [\"12198164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Ifrd1-deficient mouse neutrophils (but not macrophages) show blunted effector function associated with decreased NF-κB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway but reduced inflammation, a phenotype dependent on haematopoietic cell expression of IFRD1.\",\n      \"method\": \"Ifrd1 knockout mice, bone marrow transplantation (haematopoietic reconstitution), NF-κB reporter assay, neutrophil functional assays, in vivo airway infection model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, haematopoietic rescue experiment, NF-κB mechanistic assay, replicated in human polymorphism data\",\n      \"pmids\": [\"19242412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIS7 (IFRD1) down-regulates beta-catenin/Tcf-4 transcriptional activity and the expression of downstream target genes (c-Myc, osteopontin/OPN) in a histone deacetylase-dependent manner. TIS7 overexpression leads to beta-catenin interaction with enzymatically active histone deacetylases. TIS7 homologous deletion in mouse embryonic fibroblasts increased TOPflash reporter activity, c-Myc, and OPN expression.\",\n      \"method\": \"TOPflash reporter assay, co-immunoprecipitation, HDAC activity assay, TIS7 knockout mouse embryonic fibroblasts, qRT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay, Co-IP with HDAC activity, KO fibroblast validation, single lab with multiple methods\",\n      \"pmids\": [\"16204248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIS7 (IFRD1) inhibits C/EBPalpha-Sp1 transcription factor module activity by specifically interfering with Sp1 transcriptional activity and preventing formation of a complex between Sp1 protein and its consensus DNA binding site, as identified by bioinformatic analysis of TIS7-regulated gene promoters and confirmed by reporter assays and electrophoretic mobility shift assay (EMSA).\",\n      \"method\": \"Bioinformatic promoter analysis, reporter assay, EMSA (Sp1-DNA binding assay)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reporter assay and EMSA in single lab, two orthogonal methods\",\n      \"pmids\": [\"15095974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIS7 (IFRD1) knockout mice display delayed injury-induced muscle regeneration and altered isometric contractile properties after crush damage. Primary myogenic satellite cells from TIS7(-/-) mice show reduced differentiation potential and fusion index in a cell-autonomous fashion, with down-regulation of MyoD, myogenin, and laminin-alpha2. Fusion potential could be rescued by TIS7 re-expression or laminin supplementation.\",\n      \"method\": \"Tis7 knockout mice (homologous recombination), muscle crush injury model, primary satellite cell culture, rescue experiment (TIS7 re-expression, laminin supplementation), immunostaining\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular and organismal phenotype, cell-autonomous rescue experiment, multiple orthogonal readouts\",\n      \"pmids\": [\"15060170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PC4/TIS7 (IFRD1) functions as a negative regulator of NF-κB in myoblasts: PC4 up-regulation induces deacetylation and nuclear export of NF-κB p65, while PC4 silencing induces p65 acetylation and nuclear import, with corresponding changes in MyoD expression. PC4 forms trimolecular complexes with p65 and HDAC3, suggesting it recruits HDAC3 to deacetylate p65. PC4 potentiates inhibition of NF-κB transcriptional activity mediated by histone deacetylases.\",\n      \"method\": \"PC4 overexpression/siRNA silencing in primary myoblasts, NF-κB reporter assay, co-immunoprecipitation (trimolecular complex), nuclear fractionation, immunostaining, in vivo muscle overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of trimolecular complex, nuclear fractionation, reporter assay, KD and OE with complementary phenotypes, single lab multiple methods\",\n      \"pmids\": [\"21127072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The TIS7/PC4 protein is a membrane-associated, non-nuclear intracellular protein (as opposed to TIS21/PC3 which is a non-nuclear soluble protein), as determined by immunohistochemistry and subcellular fractionation. Pulse-chase experiments demonstrate TIS7/PC4 protein is degraded more slowly than TIS21/PC3. Secretion of TIS7/PC4 protein could not be detected.\",\n      \"method\": \"Immunohistochemistry, subcellular fractionation, pulse-chase radiolabeling, immunoprecipitation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation and immunostaining with functional context, single lab, two orthogonal methods\",\n      \"pmids\": [\"8263025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IFRD1 mRNA stability is regulated post-transcriptionally by an upstream open reading frame (uORF): translation of the uORF in resting cells promotes instability of the major ORF mRNA. During cellular stress (ER stress via tunicamycin), eIF2alpha phosphorylation inhibits translational initiation, stabilizing the IFRD1 mRNA and elevating IFRD1 protein. The instability mechanism depends on UPF1 (nonsense-mediated decay pathway), and is determined by uORF sequence and length but not by a specific encoded peptide.\",\n      \"method\": \"Tunicamycin treatment, mRNA stability assay, reporter constructs with uORF mutations, eIF2alpha phosphorylation analysis, UPF1 knockdown, polysome profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple uORF mutant constructs, UPF1 KD, polysome analysis, mechanistically detailed single lab study\",\n      \"pmids\": [\"20080976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ifrd1 (IFRD1) regulates osteoclast differentiation through the NF-κB/NFATc1 pathway: Ifrd1 deficiency increases acetylation of p65 at residues K122 and K123 via inhibition of histone deacetylase-dependent deacetylation in bone marrow macrophages, thereby repressing NF-κB-dependent transcription of NFATc1. Global Ifrd1 deletion in mice increased bone mass by decreasing bone resorption. Ifrd1 expression in preosteoclasts is transcriptionally regulated by RANKL through activator protein 1.\",\n      \"method\": \"Ifrd1 knockout mice, bone marrow macrophage osteoclastogenesis assay, p65 acetylation analysis (site-specific K122/K123), HDAC inhibitor treatment, NFATc1 reporter assay, microCT bone analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with bone phenotype, site-specific acetylation mapping, HDAC-dependence shown, reporter assay, multiple methods single lab\",\n      \"pmids\": [\"27381458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TIS7 (IFRD1) inhibits adipogenesis by promoting Wnt/β-catenin signaling: TIS7 overexpression in 3T3-L1 cells inhibits adipogenic gene expression, and this effect requires Wnt/β-catenin activity (abolished by dominant-negative TCF4). Under hypoxia, TIS7 predominantly interacts with β-catenin in the nucleus of adipose tissue. TIS7 expression is induced by hypoxia via ATF6-dependent transcriptional activation of the TIS7 promoter.\",\n      \"method\": \"TIS7 overexpression/shRNA knockdown in 3T3-L1 cells, co-immunoprecipitation (TIS7–β-catenin), reporter assay, dominant-negative TCF4, ATF6 shRNA knockdown, Oil Red O staining, in vivo ob/ob mouse model\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, DN rescue, ATF6 KD, multiple readouts, single lab\",\n      \"pmids\": [\"23517917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TIS7 (IFRD1) directly binds DNA and controls a transcriptional cascade involving ICln and PRMT5. TIS7/ICln epigenetically regulate MyoD expression via symmetrical di-methylation of histone H3 on arginine 8 through PRMT5 activity, thereby controlling skeletal muscle differentiation.\",\n      \"method\": \"ChIP (direct DNA binding), co-immunoprecipitation (TIS7-ICln-PRMT5), histone methylation assay (H3R8me2s), MyoD expression analysis, myoblast differentiation assay\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct DNA binding, Co-IP, histone modification assay, single lab with multiple methods\",\n      \"pmids\": [\"27782840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ifrd1 (IFRD1) negatively regulates thermogenic and mitochondrial gene expression (including PGC-1α/Pgc1a) in brown adipocytes by forming a complex with Sp1 and mSIN3B (a component of the histone deacetylase-containing SIN complex) upon adrenergic stimulation. Ifrd1 represses Sp1-mediated Pgc1a promoter activity in an HDAC-dependent manner (reversed by trichostatin A). Adrenergic stimulation induces Ifrd1 expression through CREB-dependent transcription.\",\n      \"method\": \"Ifrd1 knockout mice, co-immunoprecipitation (Ifrd1-Sp1-mSIN3B complex), Pgc1a promoter-reporter assay, trichostatin A treatment, CL-316243 in vivo administration, CREB analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of trimolecular complex, HDAC-dependence via TSA, KO mouse, reporter assay, single lab\",\n      \"pmids\": [\"28107769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ifrd1 (IFRD1) is a transcriptional corepressor that suppresses p65 nuclear translocation; its proteasomal degradation (induced by oridonin treatment) abolishes this suppression and allows p65 nuclear entry. Ifrd1 deficiency in osteoclast precursors increases p65 K122/K123 acetylation via HDAC inhibition, blunting NF-κB signaling. Oridonin-induced Ifrd1 degradation also promotes Smad1/Smad5 phosphorylation and osteoblast differentiation.\",\n      \"method\": \"Proteasomal degradation assay, p65 nuclear localization immunofluorescence, Ifrd1 KO osteoclast precursors, IκBα phosphorylation assay, Smad1/5 phosphorylation assay, ovariectomy mouse model\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteasomal degradation shown, nuclear localization assay, p65 acetylation, KO model, single lab\",\n      \"pmids\": [\"29091322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFRD1 promotes adaptive survival of hepatocellular carcinoma cells under glutamine starvation by inhibiting autophagy via promoting proteasomal degradation of the autophagy regulator ATG14 in a TRIM21-dependent manner. IFRD1 depletion under glutamine starvation increases autophagy flux, leading to nucleophagic degradation of histone H1.0, unchecked ribosome/protein biosynthesis, and cancer cell death. IFRD1 and TRIM21 interact (shown by co-IP), and IFRD1 prevents ATG14 from sustaining autophagy.\",\n      \"method\": \"IFRD1 knockdown/overexpression in HCC cells, glutamine starvation, co-immunoprecipitation (IFRD1-TRIM21), ATG14 proteasomal degradation assay, autophagy flux assay, nucleophagy (histone H1.0 degradation) assay, preclinical HCC models with CB-839\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, proteasomal degradation, autophagy flux, multiple cell and in vivo models, single lab\",\n      \"pmids\": [\"38802351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFRD1 interacts with mRNA-translation-regulating factors in human urothelial cells. Loss of Ifrd1 in mouse bladder leads to disrupted proteostasis, enhanced ER stress with activation of the PERK arm of the unfolded protein response, increased oxidative stress, urothelial cell apoptosis/exfoliation, enhanced basal cell proliferation, reduced differentiation into superficial cells, increased urothelial permeability, and aberrant voiding behavior.\",\n      \"method\": \"Ifrd1 knockout mice, co-immunoprecipitation (IFRD1 with translation factors), transcriptome analysis (RNA-seq), electron microscopy (organelle accumulation), UPR/PERK pathway analysis, voiding behavior assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype, Co-IP for interaction, pathway analysis, multiple readouts, single lab\",\n      \"pmids\": [\"39628564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ifrd1 (IFRD1) controls Wnt signaling and thereby transcriptionally regulates Dlk1 (a negative regulator of adipogenesis), while its paralogue Ifrd2 acts as a translational inhibitor of Dlk1 protein levels. Double knockout (dKO) mice lacking both Ifrd1 and Ifrd2 have severely reduced adipose tissue, resistance to high-fat diet-induced obesity, upregulated Wnt/β-catenin signaling, elevated Dlk1, and reduced Pparg, Cebpa, and Cd36 expression.\",\n      \"method\": \"Ifrd1/Ifrd2 double knockout mice, Wnt/β-catenin pathway analysis, Dlk1 transcription and translation assays, high-fat diet feeding, adipose tissue histology, qRT-PCR, immunoblot\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double KO mouse with defined phenotype, separate transcriptional (Ifrd1) vs translational (Ifrd2) mechanism dissected, single lab\",\n      \"pmids\": [\"37603466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IFRD1 stabilizes SLC25A5 (mitochondrial ADP/ATP translocator) by competing with the E3 ubiquitin ligase TRIM21, thereby sustaining hepatocyte β-oxidation and mitochondrial ATP production. This ATP boost enables chromatin remodeling that promotes CCL/CXC chemokine expression, recruiting CCR2+ monocytes and expanding the regenerative GPNMB+ macrophage pool to facilitate liver regeneration. Hepatocyte-specific IFRD1 loss impairs liver repair while IFRD1 overexpression enhances regeneration across multiple models.\",\n      \"method\": \"Hepatocyte-specific IFRD1 KO and AAV-mediated overexpression, Co-IP (IFRD1-SLC25A5-TRIM21), mitochondrial ATP production assay, β-oxidation assay, ATAC-seq, single-nucleus RNA-seq, partial hepatectomy and toxic liver injury models\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO, Co-IP protein interactions, metabolic assays, chromatin assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41861961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IFRD1 is primarily a cytosolic ribosome-binding protein that specifically binds 80S monosomes not actively engaged in translation. During ER stress (tunicamycin) and in vivo injury (cerulein-induced pancreatitis), IFRD1 acts as a ribosome-salvaging factor preventing ribosomes from disassembly and selective degradation. In IFRD1-deficient cells, non-translating 80S ribosomes are unstable, degrade, accumulate as p62-tagged cargo overwhelming autophagy, reduce mTORC1 activity, and increase cell death.\",\n      \"method\": \"Polysome/ribosome fractionation, IFRD1 KO cells and mice, cerulein pancreatitis model, tunicamycin ER stress model, p62 autophagy assay, mTORC1 activity assay, ribosome stability assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome fractionation, multiple in vivo and in vitro models, mTORC1 readout, single lab preprint not yet peer-reviewed\",\n      \"pmids\": [\"42146531\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IFRD1 promotes GLUD1 mitochondrial localization via direct protein-protein interaction, stabilizing GLUD1 enzyme activity to enhance α-ketoglutarate (α-KG) production. Elevated α-KG reduces H3K36me3 levels at lipogenic gene loci, inhibiting de novo lipogenesis and ameliorating metabolic steatohepatitis (MASH). Ifrd1 knockout mice exhibit exacerbated MASLD; α-KG supplementation reverses this phenotype.\",\n      \"method\": \"Co-immunoprecipitation (IFRD1-GLUD1), GLUD1 enzymatic activity assay, mitochondrial fractionation, α-KG metabolite measurement, H3K36me3 ChIP-seq at lipogenic genes, Ifrd1 conditional KO mice, MASLD mouse models, α-KG rescue experiment\",\n      \"journal\": \"Science bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction by Co-IP, enzyme activity assay, ChIP-seq for histone marks, KO with rescue, multiple methods single lab\",\n      \"pmids\": [\"41997855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BMP-2 directly induces Ifrd1 expression at the transcriptional level in osteoblasts via the Smad pathway: BMP-2 stimulation induces recruitment of Smad1 to the Ifrd1 promoter (which contains conserved Smad-binding elements), and co-introduction of Smad1 and Smad4 increases Ifrd1 promoter activity. Ifrd1 knockdown in osteoblasts enhanced BMP-2-dependent osteoblastogenesis, indicating Ifrd1 negatively feeds back on this process.\",\n      \"method\": \"ChIP (Smad1 recruitment to Ifrd1 promoter), Ifrd1 promoter-reporter assay, Smad1/4 co-transfection, LDN193189 inhibitor, Ifrd1 siRNA knockdown, Alizarin Red staining, marker gene qRT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and promoter reporter assay, KD with functional readout, single lab\",\n      \"pmids\": [\"27856249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MTHFD2 increases m6A methylation of IFRD1 RNA, which upregulates IFRD1 protein expression and activates the HDAC3/p53/mTOR pathway, promoting breast cancer cell proliferation. IFRD1 siRNA transfection reversed the proliferative effects of MTHFD2 overexpression, placing IFRD1 downstream of MTHFD2-mediated m6A modification.\",\n      \"method\": \"MTHFD2 overexpression/knockdown, m6A methylation assay on IFRD1 mRNA, IFRD1 siRNA rescue, cell proliferation assay (EdU), cell cycle analysis, HDAC3/p53/mTOR pathway western blot\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, m6A assay and rescue experiment but limited mechanistic depth on IFRD1's direct action\",\n      \"pmids\": [\"39832202\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFRD1/TIS7 is a stress-responsive, histone-deacetylase-dependent transcriptional co-regulator that assembles with the SIN3–HDAC complex (via mSin3B, HDAC1/3, N-CoR, SAP30) to repress specific gene sets; it modulates NF-κB p65 transactivation by recruiting HDAC3 to promote p65 deacetylation and nuclear export, controls skeletal muscle differentiation via MyoD (through an ICln/PRMT5-H3R8me2s epigenetic axis and NF-κB suppression), inhibits Wnt/β-catenin target genes and adipogenesis, regulates osteoclastogenesis through an Ifrd1/NF-κB/NFATc1 axis, stabilizes mitochondrial SLC25A5 (competing with TRIM21 ubiquitin ligase) to sustain ATP production and chromatin remodeling in hepatocytes, promotes GLUD1 mitochondrial localization to enhance α-KG production and suppress lipogenic gene chromatin marks, and in the cytosol binds non-translating 80S ribosomes to protect them from stress-induced disassembly and degradation, thereby preserving mTORC1 activity and cell survival during metabolic transitions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFRD1 (TIS7/PC4) is a stress-responsive, histone-deacetylase-dependent transcriptional co-regulator that couples cellular stress signals to repression of defined gene programs across differentiation, immunity, and metabolism [#0, #1]. It assembles with the mammalian SIN3–HDAC complex, interacting with mSin3B, HDAC1, N-CoR, and SAP30 to deliver enzymatically active deacetylase activity to target promoters [#0]. A recurring mechanistic theme is its control of NF-κB: IFRD1 forms trimolecular complexes with p65 and HDAC3, driving p65 deacetylation and nuclear export, and its loss elevates p65 K122/K123 acetylation, thereby tuning NF-κB-dependent transcription in neutrophils, myoblasts, and osteoclast precursors [#1, #5, #8]. Through HDAC-dependent and direct DNA-binding routes it represses Wnt/β-catenin–TCF target genes (c-Myc, osteopontin) and Sp1-driven programs [#2, #3, #10, #11]. These activities position IFRD1 as a controller of skeletal muscle regeneration via MyoD, acting partly through an ICln/PRMT5 H3R8me2s epigenetic axis [#4, #10], of osteoclast differentiation via an NF-κB/NFATc1 axis [#8], and of adipogenesis and thermogenic gene expression [#9, #11, #15]. IFRD1 expression is itself stress-gated: an upstream ORF destabilizes its mRNA via UPF1-dependent decay in resting cells, while eIF2α phosphorylation during ER stress stabilizes the transcript and elevates protein [#7]. Beyond transcription, IFRD1 has cytoplasmic functions, stabilizing the mitochondrial proteins SLC25A5 and GLUD1 by competing with the TRIM21 ubiquitin ligase to sustain ATP production, β-oxidation, and α-ketoglutarate–dependent chromatin remodeling in hepatocytes [#16, #18], and acting as a cytosolic ribosome-salvaging factor that binds non-translating 80S monosomes to protect them from stress-induced degradation, preserving mTORC1 activity and survival [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the basic cell biology of the TIS7/PC4 protein before any molecular activity was known, distinguishing it as a stable, membrane-associated intracellular protein.\",\n      \"evidence\": \"Immunohistochemistry, subcellular fractionation, and pulse-chase radiolabeling\",\n      \"pmids\": [\"8263025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned\", \"Localization later refined to nuclear and cytosolic compartments by other studies\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Answered what IFRD1 does molecularly by identifying it as a SIN3–HDAC-associated transcriptional co-repressor, defining its core mechanism of action.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP with HDAC enzymatic activity assay, and reporter assay in mammary epithelial cells\",\n      \"pmids\": [\"12198164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA binding not established at this stage\", \"Specific endogenous target genes not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected IFRD1's co-repressor activity to a physiological program by showing it is required cell-autonomously for muscle differentiation and regeneration via MyoD/myogenin.\",\n      \"evidence\": \"Tis7 knockout mice, muscle crush injury, primary satellite cell culture with rescue\",\n      \"pmids\": [\"15060170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between co-repressor function and MyoD induction not yet defined\", \"Laminin-alpha2 regulation mechanism unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified Sp1 as a specific transcriptional target of IFRD1 interference, broadening its repertoire beyond generic HDAC recruitment.\",\n      \"evidence\": \"Bioinformatic promoter analysis, reporter assay, and EMSA\",\n      \"pmids\": [\"15095974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IFRD1 binds Sp1 directly versus blocking DNA occupancy indirectly not fully resolved\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed IFRD1 represses Wnt/β-catenin–TCF target genes in an HDAC-dependent manner, defining a pathway-level repression target.\",\n      \"evidence\": \"TOPflash reporter, co-IP, HDAC activity assay, and TIS7 knockout MEFs\",\n      \"pmids\": [\"16204248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of β-catenin–HDAC bridging not structurally defined\", \"Direct versus indirect recruitment unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated a physiological immune role, with IFRD1 required for neutrophil effector function through NF-κB p65 transactivation in vivo.\",\n      \"evidence\": \"Ifrd1 knockout mice, haematopoietic reconstitution, NF-κB reporter, airway infection model\",\n      \"pmids\": [\"19242412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular mechanism of p65 regulation not yet mapped\", \"Neutrophil-specific target genes not enumerated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the molecular mechanism of NF-κB regulation: IFRD1 recruits HDAC3 to p65, driving its deacetylation and nuclear export.\",\n      \"evidence\": \"Overexpression/silencing in myoblasts, co-IP of p65-HDAC3 trimolecular complex, nuclear fractionation\",\n      \"pmids\": [\"21127072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site-specific p65 residues deacetylated not yet mapped in this study\", \"Stoichiometry of the complex unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Explained how IFRD1 itself is stress-induced, identifying a uORF/UPF1-dependent decay mechanism relieved by eIF2α phosphorylation during ER stress.\",\n      \"evidence\": \"Tunicamycin treatment, uORF mutant reporters, UPF1 knockdown, polysome profiling, eIF2α phosphorylation analysis\",\n      \"pmids\": [\"20080976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stabilized protein localizes to specific compartments under stress not addressed\", \"Link to downstream functional outputs not tested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended IFRD1's Wnt control to metabolism, showing hypoxia/ATF6-induced IFRD1 promotes Wnt signaling to inhibit adipogenesis.\",\n      \"evidence\": \"3T3-L1 overexpression/knockdown, TIS7–β-catenin co-IP, dominant-negative TCF4, ATF6 knockdown, ob/ob model\",\n      \"pmids\": [\"23517917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent context-dependent activation versus repression of Wnt not reconciled\", \"Direct β-catenin binding interface undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the muscle differentiation mechanism by showing IFRD1 binds DNA directly and uses an ICln/PRMT5 H3R8me2s axis to control MyoD.\",\n      \"evidence\": \"ChIP for direct DNA binding, co-IP of TIS7-ICln-PRMT5, H3R8me2s histone methylation assay\",\n      \"pmids\": [\"27782840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DNA sequence specificity of IFRD1 binding not defined\", \"How HDAC and PRMT5 activities are coordinated unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped IFRD1's role in bone, defining an NF-κB/NFATc1 axis via site-specific p65 K122/K123 deacetylation controlling osteoclastogenesis.\",\n      \"evidence\": \"Ifrd1 knockout mice, bone marrow macrophage osteoclastogenesis, site-specific acetylation analysis, microCT\",\n      \"pmids\": [\"27381458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which HDAC executes K122/K123 deacetylation in this context not specified\", \"Direct IFRD1 promoter targets in osteoclasts not enumerated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed IFRD1 in a negative feedback loop on osteoblast differentiation, induced transcriptionally by BMP-2/Smad signaling.\",\n      \"evidence\": \"ChIP of Smad1 at Ifrd1 promoter, promoter-reporter, Smad1/4 co-transfection, siRNA knockdown\",\n      \"pmids\": [\"27856249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream IFRD1 targets opposing osteoblastogenesis not identified\", \"Interplay with osteoclast role in intact bone not integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed IFRD1 represses thermogenic and mitochondrial genes by forming an Sp1–mSIN3B complex on the Pgc1a promoter, linking it to brown fat function.\",\n      \"evidence\": \"Ifrd1 knockout mice, co-IP of Ifrd1-Sp1-mSIN3B, Pgc1a promoter-reporter, TSA treatment, CREB analysis\",\n      \"pmids\": [\"28107769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA contact versus Sp1-tethered recruitment at Pgc1a unresolved\", \"Systemic energy expenditure consequences not fully quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked IFRD1 protein stability to function, showing proteasomal degradation relieves its suppression of p65 and shifts the osteoclast/osteoblast balance.\",\n      \"evidence\": \"Proteasomal degradation (oridonin) assay, p65 nuclear localization imaging, Ifrd1 KO precursors, Smad1/5 phosphorylation, ovariectomy model\",\n      \"pmids\": [\"29091322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating IFRD1 degradation not identified here\", \"Specificity of oridonin for IFRD1 not fully isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Dissected divergent IFRD1 versus IFRD2 mechanisms, with IFRD1 controlling Dlk1 transcriptionally via Wnt to restrain adipose development.\",\n      \"evidence\": \"Ifrd1/Ifrd2 double knockout mice, Wnt pathway analysis, Dlk1 transcription/translation assays, high-fat diet feeding\",\n      \"pmids\": [\"37603466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IFRD1 occupancy at the Dlk1 locus not shown\", \"Functional redundancy boundaries between paralogues incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a cytoplasmic, TRIM21-dependent function: IFRD1 promotes ATG14 degradation to restrain autophagy and enable HCC survival under glutamine starvation.\",\n      \"evidence\": \"IFRD1 knockdown/overexpression in HCC, IFRD1-TRIM21 co-IP, ATG14 degradation, autophagy/nucleophagy flux assays, CB-839 models\",\n      \"pmids\": [\"38802351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How IFRD1 directs TRIM21 toward ATG14 mechanistically unclear\", \"Relationship to nuclear co-repressor role not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected IFRD1 to proteostasis and translation, showing its loss triggers PERK-arm UPR activation and urothelial differentiation/permeability defects.\",\n      \"evidence\": \"Ifrd1 knockout mice, co-IP with translation factors, RNA-seq, electron microscopy, UPR/PERK analysis, voiding assay\",\n      \"pmids\": [\"39628564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the interacting translation factors not specified\", \"Direct molecular role in translation versus transcription not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed IFRD1 downstream of MTHFD2-driven m6A modification feeding an HDAC3/p53/mTOR proliferative axis in breast cancer.\",\n      \"evidence\": \"MTHFD2 overexpression/knockdown, m6A assay on IFRD1 mRNA, IFRD1 siRNA rescue, proliferation and pathway analysis\",\n      \"pmids\": [\"39832202\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic depth on IFRD1's direct action in this axis\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a mitochondrial metabolic function: IFRD1 stabilizes SLC25A5 by competing with TRIM21 to sustain ATP and chromatin remodeling supporting liver regeneration.\",\n      \"evidence\": \"Hepatocyte-specific KO and AAV overexpression, IFRD1-SLC25A5-TRIM21 co-IP, ATP/β-oxidation assays, ATAC-seq, snRNA-seq, hepatectomy models\",\n      \"pmids\": [\"41861961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of competition with TRIM21 unresolved\", \"Generality of metabolic stabilization across tissues untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed IFRD1 promotes GLUD1 mitochondrial localization to raise α-KG and lower H3K36me3 at lipogenic genes, ameliorating steatohepatitis.\",\n      \"evidence\": \"IFRD1-GLUD1 co-IP, GLUD1 activity assay, α-KG measurement, H3K36me3 ChIP-seq, conditional KO with α-KG rescue\",\n      \"pmids\": [\"41997855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction interface with GLUD1 not mapped\", \"Whether α-KG effect is solely via histone demethylation unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a translation-protective role: cytosolic IFRD1 binds non-translating 80S ribosomes to salvage them from stress-induced degradation, preserving mTORC1 and survival.\",\n      \"evidence\": \"Polysome/ribosome fractionation, IFRD1 KO cells and mice, cerulein and tunicamycin stress models, p62 and mTORC1 assays (preprint)\",\n      \"pmids\": [\"42146531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structural basis of 80S monosome recognition undefined\", \"Reconciliation of cytosolic ribosome role with nuclear co-repressor role open\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFRD1's distinct nuclear (SIN3-HDAC co-repressor), mitochondrial (SLC25A5/GLUD1 stabilization), and cytosolic (ribosome salvage) activities are partitioned and coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of IFRD1 domains assigned to each function\", \"Signals dictating compartment-specific deployment unknown\", \"Whether TRIM21 competition is a unifying mechanism across substrates untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 8, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 8, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"SIN3-HDAC complex\"],\n    \"partners\": [\"SIN3B\", \"HDAC1\", \"HDAC3\", \"NCOR1\", \"SAP30\", \"TRIM21\", \"SLC25A5\", \"GLUD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}