Affinage

IFRD1

Interferon-related developmental regulator 1 · UniProt O00458

Length
451 aa
Mass
50.3 kDa
Annotated
2026-06-10
44 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 Medium

    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

    PMID:8263025

    Open questions at the time
    • No molecular function assigned
    • Localization later refined to nuclear and cytosolic compartments by other studies
  2. 2002 High

    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

    PMID:12198164

    Open questions at the time
    • Direct DNA binding not established at this stage
    • Specific endogenous target genes not defined
  3. 2004 High

    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

    PMID:15060170

    Open questions at the time
    • Molecular link between co-repressor function and MyoD induction not yet defined
    • Laminin-alpha2 regulation mechanism unresolved
  4. 2004 Medium

    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

    PMID:15095974

    Open questions at the time
    • Whether IFRD1 binds Sp1 directly versus blocking DNA occupancy indirectly not fully resolved
    • No in vivo validation
  5. 2005 Medium

    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

    PMID:16204248

    Open questions at the time
    • Mechanism of β-catenin–HDAC bridging not structurally defined
    • Direct versus indirect recruitment unresolved
  6. 2009 High

    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

    PMID:19242412

    Open questions at the time
    • Direct molecular mechanism of p65 regulation not yet mapped
    • Neutrophil-specific target genes not enumerated
  7. 2010 High

    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

    PMID:21127072

    Open questions at the time
    • Site-specific p65 residues deacetylated not yet mapped in this study
    • Stoichiometry of the complex unresolved
  8. 2010 High

    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

    PMID:20080976

    Open questions at the time
    • Whether stabilized protein localizes to specific compartments under stress not addressed
    • Link to downstream functional outputs not tested here
  9. 2013 Medium

    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

    PMID:23517917

    Open questions at the time
    • Apparent context-dependent activation versus repression of Wnt not reconciled
    • Direct β-catenin binding interface undefined
  10. 2016 Medium

    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

    PMID:27782840

    Open questions at the time
    • DNA sequence specificity of IFRD1 binding not defined
    • How HDAC and PRMT5 activities are coordinated unclear
  11. 2016 High

    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

    PMID:27381458

    Open questions at the time
    • Which HDAC executes K122/K123 deacetylation in this context not specified
    • Direct IFRD1 promoter targets in osteoclasts not enumerated
  12. 2016 Medium

    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

    PMID:27856249

    Open questions at the time
    • Downstream IFRD1 targets opposing osteoblastogenesis not identified
    • Interplay with osteoclast role in intact bone not integrated
  13. 2017 Medium

    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

    PMID:28107769

    Open questions at the time
    • Direct DNA contact versus Sp1-tethered recruitment at Pgc1a unresolved
    • Systemic energy expenditure consequences not fully quantified
  14. 2018 Medium

    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

    PMID:29091322

    Open questions at the time
    • E3 ligase mediating IFRD1 degradation not identified here
    • Specificity of oridonin for IFRD1 not fully isolated
  15. 2023 Medium

    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

    PMID:37603466

    Open questions at the time
    • Direct IFRD1 occupancy at the Dlk1 locus not shown
    • Functional redundancy boundaries between paralogues incompletely defined
  16. 2024 Medium

    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

    PMID:38802351

    Open questions at the time
    • How IFRD1 directs TRIM21 toward ATG14 mechanistically unclear
    • Relationship to nuclear co-repressor role not integrated
  17. 2024 Medium

    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

    PMID:39628564

    Open questions at the time
    • Identity of the interacting translation factors not specified
    • Direct molecular role in translation versus transcription not separated
  18. 2024 Low

    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

    PMID:39832202

    Open questions at the time
    • Limited mechanistic depth on IFRD1's direct action in this axis
    • Single lab, not independently confirmed
  19. 2026 Medium

    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

    PMID:41861961

    Open questions at the time
    • Structural basis of competition with TRIM21 unresolved
    • Generality of metabolic stabilization across tissues untested
  20. 2026 Medium

    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

    PMID:41997855

    Open questions at the time
    • Direct interaction interface with GLUD1 not mapped
    • Whether α-KG effect is solely via histone demethylation unresolved
  21. 2026 Medium

    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)

    PMID:42146531

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Structural basis of 80S monosome recognition undefined
    • Reconciliation of cytosolic ribosome role with nuclear co-repressor role open

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1 GO:0005840 ribosome 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2 R-HSA-8953854 Metabolism of RNA 1 R-HSA-9612973 Autophagy 1
Partners
GLUD1HDAC1HDAC3NCOR1SAP30SIN3BSLC25A5TRIM21
Complex memberships
SIN3-HDAC complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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. Yeast two-hybrid screening, co-immunoprecipitation, HDAC enzymatic activity assay, cDNA microarray, immunofluorescence The EMBO journal High 12198164
2009 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. Ifrd1 knockout mice, bone marrow transplantation (haematopoietic reconstitution), NF-κB reporter assay, neutrophil functional assays, in vivo airway infection model Nature High 19242412
2005 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. TOPflash reporter assay, co-immunoprecipitation, HDAC activity assay, TIS7 knockout mouse embryonic fibroblasts, qRT-PCR The Journal of biological chemistry Medium 16204248
2004 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). Bioinformatic promoter analysis, reporter assay, EMSA (Sp1-DNA binding assay) Journal of molecular biology Medium 15095974
2004 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. Tis7 knockout mice (homologous recombination), muscle crush injury model, primary satellite cell culture, rescue experiment (TIS7 re-expression, laminin supplementation), immunostaining Molecular and cellular biology High 15060170
2010 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. PC4 overexpression/siRNA silencing in primary myoblasts, NF-κB reporter assay, co-immunoprecipitation (trimolecular complex), nuclear fractionation, immunostaining, in vivo muscle overexpression The Journal of biological chemistry High 21127072
1994 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. Immunohistochemistry, subcellular fractionation, pulse-chase radiolabeling, immunoprecipitation Journal of cellular physiology Medium 8263025
2010 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. Tunicamycin treatment, mRNA stability assay, reporter constructs with uORF mutations, eIF2alpha phosphorylation analysis, UPF1 knockdown, polysome profiling The Journal of biological chemistry High 20080976
2016 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. Ifrd1 knockout mice, bone marrow macrophage osteoclastogenesis assay, p65 acetylation analysis (site-specific K122/K123), HDAC inhibitor treatment, NFATc1 reporter assay, microCT bone analysis Molecular and cellular biology High 27381458
2013 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. 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 Biochimica et biophysica acta Medium 23517917
2016 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. ChIP (direct DNA binding), co-immunoprecipitation (TIS7-ICln-PRMT5), histone methylation assay (H3R8me2s), MyoD expression analysis, myoblast differentiation assay BMC biology Medium 27782840
2017 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. Ifrd1 knockout mice, co-immunoprecipitation (Ifrd1-Sp1-mSIN3B complex), Pgc1a promoter-reporter assay, trichostatin A treatment, CL-316243 in vivo administration, CREB analysis The FEBS journal Medium 28107769
2018 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. Proteasomal degradation assay, p65 nuclear localization immunofluorescence, Ifrd1 KO osteoclast precursors, IκBα phosphorylation assay, Smad1/5 phosphorylation assay, ovariectomy mouse model Journal of bone and mineral research Medium 29091322
2024 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. 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 Cell discovery Medium 38802351
2024 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. Ifrd1 knockout mice, co-immunoprecipitation (IFRD1 with translation factors), transcriptome analysis (RNA-seq), electron microscopy (organelle accumulation), UPR/PERK pathway analysis, voiding behavior assay iScience Medium 39628564
2023 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. 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 eLife Medium 37603466
2026 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. 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 of hepatology Medium 41861961
2026 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. Polysome/ribosome fractionation, IFRD1 KO cells and mice, cerulein pancreatitis model, tunicamycin ER stress model, p62 autophagy assay, mTORC1 activity assay, ribosome stability assay bioRxivpreprint Medium 42146531
2026 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. 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 Science bulletin Medium 41997855
2016 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. 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 Biochemical and biophysical research communications Medium 27856249
2024 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. 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 Neoplasma Low 39832202

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 97 19242412
2010 PC4/Tis7/IFRD1 stimulates skeletal muscle regeneration and is involved in myoblast differentiation as a regulator of MyoD and NF-kappaB. The Journal of biological chemistry 60 21127072
2018 A Novel Diterpenoid Suppresses Osteoclastogenesis and Promotes Osteogenesis by Inhibiting Ifrd1-Mediated and IκBα-Mediated p65 Nuclear Translocation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 56 29091322
1989 Characterization of TIS7, a gene induced in Swiss 3T3 cells by the tumor promoter tetradecanoyl phorbol acetate. Oncogene 41 2797820
2004 Muscle regeneration and myogenic differentiation defects in mice lacking TIS7. Molecular and cellular biology 40 15060170
1994 Synthesis, degradation, and subcellular localization of proteins encoded by the primary response genes TIS7/PC4 and TIS21/PC3. Journal of cellular physiology 40 8263025
2002 TIS7 interacts with the mammalian SIN3 histone deacetylase complex in epithelial cells. The EMBO journal 39 12198164
2009 IFRD1 is a candidate gene for SMNA on chromosome 7q22-q23. American journal of human genetics 35 19409521
2010 Stress-sensitive regulation of IFRD1 mRNA decay is mediated by an upstream open reading frame. The Journal of biological chemistry 34 20080976
1998 Cloning of the human interferon-related developmental regulator (IFRD1) gene coding for the PC4 protein, a member of a novel family of developmentally regulated genes. Genomics 30 9722946
2005 TIS7 regulation of the beta-catenin/Tcf-4 target gene osteopontin (OPN) is histone deacetylase-dependent. The Journal of biological chemistry 29 16204248
1998 Use of differential display reverse transcription-PCR to reveal cellular changes during stimuli that result in herpes simplex virus type 1 reactivation from latency: upregulation of immediate-early cellular response genes TIS7, interferon, and interferon regulatory factor-1. Journal of virology 27 9445025
2016 Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway. Molecular and cellular biology 26 27381458
2013 Repression of adipogenesis through promotion of Wnt/β-catenin signaling by TIS7 up-regulated in adipocytes under hypoxia. Biochimica et biophysica acta 26 23517917
1998 Regulation of PC4/TIS7 expression in adapting remnant intestine after resection. The American journal of physiology 25 9724262
2005 Targeted intestinal overexpression of the immediate early gene tis7 in transgenic mice increases triglyceride absorption and adiposity. The Journal of biological chemistry 24 16085642
1997 The human homolog of the rodent immediate early response genes, PC4 and TIS7, resides in the lung cancer tumor suppressor gene region on chromosome 3p21. Human genetics 24 9050919
2007 Role of TIS7 family of transcriptional regulators in differentiation and regeneration. Differentiation; research in biological diversity 23 17634072
2003 Growth factor regulation of PC4/TIS7, an immediate early gene expressed during gut adaptation after resection. JPEN. Journal of parenteral and enteral nutrition 19 12665168
2024 IFRD1 promotes tumor cells "low-cost" survival under glutamine starvation via inhibiting histone H1.0 nucleophagy. Cell discovery 18 38802351
2010 Deletion of Tis7 protects mice from high-fat diet-induced weight gain and blunts the intestinal adaptive response postresection. The Journal of nutrition 17 20861213
2017 The transcriptional modulator Ifrd1 controls PGC-1α expression under short-term adrenergic stimulation in brown adipocytes. The FEBS journal 16 28107769
2004 Inhibitory effect of TIS7 on Sp1-C/EBPalpha transcription factor module activity. Journal of molecular biology 14 15095974
2023 The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15). eLife 12 37603466
2017 Increased IFRD1 Expression in Human Colon Cancers Predicts Reduced Patient Survival. Digestive diseases and sciences 10 29094309
2014 Tis7 deletion reduces survival and induces intestinal anastomotic inflammation and obstruction in high-fat diet-fed mice with short bowel syndrome. American journal of physiology. Gastrointestinal and liver physiology 9 25059825
2020 IFRD1 regulates the asthmatic responses of airway via NF-κB pathway. Molecular immunology 8 32992150
2015 IFRD1 gene polymorphisms are associated with nasal polyposis in cystic fibrosis patients. Rhinology 8 26397160
2011 Reduced expression of Tis7/IFRD1 protein in murine and human cystic fibrosis airway epithelial cell models homozygous for the F508del-CFTR mutation. Biochemical and biophysical research communications 8 21723850
2016 Expression and regulation of the differentiation regulators ERBB Receptor Feedback Inhibitor 1 (ERRFI1) and Interferon-related Developmental Regulator 1 (IFRD1) during the periovulatory period in the rat ovary. Molecular reproduction and development 7 27358163
2018 Identification of IFRD1 variant in a Han Chinese family with autosomal dominant hereditary spastic paraplegia associated with peripheral neuropathy and ataxia. Journal of human genetics 6 29362493
2016 The transcriptional modulator Ifrd1 is a negative regulator of BMP-2-dependent osteoblastogenesis. Biochemical and biophysical research communications 5 27856249
2024 IFRD1 is required for maintenance of bladder epithelial homeostasis. iScience 4 39628564
2016 TIS7 induces transcriptional cascade of methylosome components required for muscle differentiation. BMC biology 4 27782840
2016 Proline Absorption and SGK1 Expression are Inhibited in Intestinal Tis7 Transgenic Mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2 27050729
2014 IFRD1 polymorphisms and gastric cancer risk in a Chinese population. Medical oncology (Northwood, London, England) 2 25073439
2026 IFRD1 orchestrates hepatocyte metabolism and macrophage interactions to facilitate liver regeneration. Journal of hepatology 1 41861961
2024 A new role for IFRD1 in regulation of ER stress in bladder epithelial homeostasis. bioRxiv : the preprint server for biology 1 38260387
2026 Multi-omics analyses related to unfolded protein response in prostate cancer implicate pro-tumor role of IFRD1. Frontiers in immunology 0 41694360
2026 Hepatic IFRD1 suppresses metabolic dysfunction-associated fatty liver disease via GLUD1/α-KG axis. Science bulletin 0 41997855
2026 Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism. bioRxiv : the preprint server for biology 0 42146531
2024 Molecular features, antiviral activity, and immunological expression assessment of interferon-related developmental regulator 1 (IFRD1) in red-spotted grouper (Epinephelus akaara). Fish & shellfish immunology 0 39182708
2024 MTHFD2 promotes breast cancer cell proliferation through IFRD1 RNA m6A methylation-mediated HDAC3/p53/mTOR pathway. Neoplasma 0 39832202
2014 [Relationship of IFRD1-rs3807213 gene polymorphism with the risk of gastric cancer among Chinese]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 24527581

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