Affinage

DDIT4

DNA damage-inducible transcript 4 protein · UniProt Q9NX09

Length
232 aa
Mass
25.4 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDIT4 (REDD1/RTP801) is a stress-inducible protein that acts as a metabolic checkpoint, principally by inhibiting mTORC1 signaling downstream of AKT to restrain cell growth and protein synthesis (PMID:15632201, PMID:16258273). Mechanistically, it suppresses mTORC1 by stabilizing and activating the TSC1-TSC2 complex, with which it physically interacts (PMID:17005863, PMID:20473305), although context-specific mTORC1 inhibition in skeletal muscle proceeds through an Akt/PRAS40 route independent of TSC2/14-3-3 modulation (PMID:25315696), and a parallel arm engages mTORC2-dependent AKT activation (PMID:34907345). Its transcription is induced by diverse stresses through a broad set of factors including HIF-1α under hypoxia and insulin signaling (PMID:11884613, PMID:19996311), Sp1 (PMID:15180327), Elk-1 and C/EBPβ in response to oxidative and DNA-damaging stress (PMID:16008523, PMID:15751966), and ATF4 under metabolic stress such as metformin and cachexia, where promoter DNA methylation by DNMT3A gates ATF4 access (PMID:34253170, PMID:39729999); it is repressed by TAL1 in hematopoietic progenitors (PMID:25858676) and induced via a p53-RFX7 axis (PMID:34907345). DDIT4 protein abundance is tightly controlled by degradation: parkin directs K48-linked polyubiquitination and NEDD4 directs K63-linked polyubiquitination for proteasomal turnover (PMID:25101677, PMID:27494837), while a redox-sensitive C150/C157 disulfide bond allosterically disrupts a degron to block HSC70-dependent chaperone-mediated autophagy and stabilize the protein under hyperglycemia (PMID:36170669). Beyond mTORC1, DDIT4 drives NF-κB-dependent inflammation through two routes—atypical sequestration of IκBα via its C-terminal Lys219/220 residues (PMID:29547704, PMID:36272977) and sustained IKK autophosphorylation/K63-ubiquitination acting downstream of GSK3β (PMID:36309088, PMID:37392853)—and amplifies ROS production in feedback loops affecting diabetic tissues and the liver (PMID:31141608, PMID:34310076). Physiologically, DDIT4 is neuroprotective acutely but pro-death when chronically elevated in post-mitotic neurons, and its elevation contributes to Parkinson's, Huntington's, and Alzheimer's disease pathology, glucocorticoid-induced muscle atrophy and lymphocyte autophagy, peripheral nerve myelination, cortical neurogenesis, tumorigenesis, and inflammatory and diabetic complications across multiple organs (PMID:17005863, PMID:19118169, PMID:21733849, PMID:21368030, PMID:24048858, PMID:32956680, PMID:32732871, PMID:34131105).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Established DDIT4 as a hypoxia-inducible gene with opposite, cell-context-dependent effects on survival, framing it as a stress-response regulator of ROS and apoptosis.

    Evidence Tetracycline-repressible overexpression with ROS and viability readouts in dividing and neuron-like cells, plus an in vivo ischemia model

    PMID:11884613

    Open questions at the time
    • No molecular target of DDIT4 identified
    • Mechanism distinguishing protective vs pro-apoptotic outcomes unresolved
  2. 2005 High

    Defined DDIT4's central molecular function: stress-induced inhibition of mTOR signaling positioned downstream of AKT and upstream of TSC2.

    Evidence Overexpression/knockdown with S6K and 4EBP1 phosphorylation assays and genetic epistasis in mammalian and Drosophila cells

    PMID:15632201 PMID:16258273

    Open questions at the time
    • Biochemical mechanism by which REDD1 activates TSC1/TSC2 not resolved
    • Stoichiometry and direct binding partners within the TSC complex unclear
  3. 2004 Medium

    Began mapping the transcriptional control of DDIT4, identifying promoter elements driving stress induction.

    Evidence Promoter deletion/mutation luciferase reporters with Sp1 antisense, Elk-1/C/EBPβ EMSA, and HIF-1α knockdown across hypoxia, arsenite, MMS and insulin stimuli

    PMID:15180327 PMID:15751966 PMID:16008523 PMID:19996311

    Open questions at the time
    • Relative contribution of each factor in physiological settings unclear
    • Combinatorial regulation across stresses not integrated
  4. 2006 High

    Linked DDIT4 mechanistically to neurodegeneration, showing its TSC2/mTOR-dependent activity drives dopaminergic neuron death in Parkinson's disease.

    Evidence Postmortem PD immunohistochemistry, shRNA knockdown, TSC2 co-immunoprecipitation, and the stress→REDD1→mTOR→p-Akt depletion sequence validated in human tissue

    PMID:17005863 PMID:19118169

    Open questions at the time
    • Trigger for sustained DDIT4 elevation in PD neurons unknown
    • Why feedback Akt dephosphorylation becomes lethal not fully defined
  5. 2010 High

    Demonstrated in vivo that DDIT4 couples mTOR inhibition to NF-κB-driven oxidative tissue injury, extending its role to inflammatory disease.

    Evidence Rtp801 knockout and forced-expression mice in a cigarette-smoke emphysema model with NF-κB reporters and mTOR readouts, plus human emphysema tissue

    PMID:20473305

    Open questions at the time
    • Direct molecular link between REDD1 and NF-κB not yet defined at this stage
    • Relationship between mTOR inhibition and NF-κB activation unclear
  6. 2011 High

    Showed DDIT4 mediates physiological stress and developmental programs beyond pathology, including glucocorticoid-induced autophagy and cortical neurogenesis timing.

    Evidence RNAi and knockout thymocytes with autophagy/mTOR readouts; in utero electroporation knockdown with BrdU and migration phenotyping

    PMID:21368030 PMID:21733849

    Open questions at the time
    • Mechanism linking mTOR inhibition to migration/differentiation not detailed
    • Cell-type determinants of pro-survival vs pro-death outcomes unresolved
  7. 2013 Medium

    Revealed post-transcriptional and spatial regulation of DDIT4 itself: an mTORC1-REDD1 stability feedback loop, peripheral myelination control, and Ca2+/calmodulin-driven plasma-membrane translocation as an inactivation mode.

    Evidence Cycloheximide chase with proteasome/E3 knockdowns; Ddit4-null nerve myelination phenotyping; BRET membrane-translocation assays with mTORC1 readouts

    PMID:23717519 PMID:24048858 PMID:24338366

    Open questions at the time
    • E3 ligase responsible for the mTORC1-dependent turnover not identified here
    • Physiological signals triggering membrane translocation in vivo unknown
  8. 2014 High

    Identified the E3 ligase parkin as a DDIT4-degrading enzyme and dissected a TSC2-independent muscle atrophy mechanism, clarifying both degradation and context-specific signaling.

    Evidence Reciprocal Co-IP and ubiquitination assays with parkin knockout models and AR-JP patient tissue; REDD1-null mice with dexamethasone-induced atrophy and Akt/PRAS40 analysis

    PMID:25101677 PMID:25315696

    Open questions at the time
    • Determinants of TSC2-dependent vs Akt/PRAS40-dependent mTORC1 inhibition unresolved
    • Whether parkin and other ligases act redundantly unclear
  9. 2016 Medium

    Established NEDD4 as a second, K63-specific E3 ligase for DDIT4 and uncovered an mTORC1-independent pro-inflammatory function of REDD1 in macrophages.

    Evidence Cell-free ubiquitination, Co-IP, linkage-specific assays, and double-knockdown epistasis; REDD1-/- BMDMs with NLRP3/cytokine and ROS readouts

    PMID:27494837 PMID:28765650

    Open questions at the time
    • Distinct functional consequences of K48 vs K63 ubiquitination not separated
    • Whether inflammatory ROS effects are upstream or downstream of mTOR unclear
  10. 2018 High

    Defined the molecular basis of atypical NF-κB activation by DDIT4, mapping a C-terminal IκBα-sequestering domain.

    Evidence Co-IP with domain mapping (aa 178-229), REDD-1 knockout macrophages, NF-κB reporters, and endotoxemia model

    PMID:29547704

    Open questions at the time
    • Structural details of the REDD1–IκBα interface not resolved
    • Reconciliation with IKK-dependent NF-κB route not yet addressed
  11. 2022 High

    Resolved DDIT4 redox-dependent stabilization and refined its two NF-κB-activation mechanisms with residue-level and signaling detail, including a GSK3β-IKK arm.

    Evidence Molecular dynamics plus C150/C157 and K129 mutagenesis with HSC70 Co-IP; Lys219/220Ala knock-in mice; REDD1-KO with IKK autophosphorylation/K63-ubiquitination and GSK3β rescue assays in diabetic models

    PMID:36170669 PMID:36272977 PMID:36309088 PMID:37392853

    Open questions at the time
    • Whether IκBα-sequestration and IKK-sustaining mechanisms operate in the same cells unclear
    • How redox state coordinates with ubiquitin-dependent turnover not integrated
  12. 2024 High

    Connected DDIT4 transcriptional control to metabolic-epigenetic regulation, showing methionine-cycle-dependent DNA methylation gates ATF4-driven DDIT4 induction in cachexia.

    Evidence DNMT3A and REDD1 knockout mice, ChIP, DNA methylation assays, and methionine supplementation rescue in cancer cachexia models

    PMID:39729999

    Open questions at the time
    • Generality of methylation gating across other DDIT4-inducing stresses unknown
    • Direct enzymatic effector of DDIT4 in cachectic muscle wasting not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DDIT4's competing degradation routes (parkin/NEDD4 proteasomal vs HSC70/CMA lysosomal), redox and S-nitrosylation states, and dual mTOR-dependent vs NF-κB/ROS-dependent activities are integrated to produce its opposite (protective vs pathogenic) outcomes in a given cell remains unresolved.
  • No unified structural model of how REDD1 engages TSC1/TSC2, IκBα, and IKK
  • Determinants selecting degradation pathway in a given stress unknown
  • Mechanism switching neuroprotective vs pro-apoptotic output undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-9612973 Autophagy 2
Partners
CHUKHSPA8NEDD4NFKBIAPARK2TSC1TSC2

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 RTP801/DDIT4 is a novel HIF-1-responsive gene whose expression is strongly upregulated by hypoxia both in vitro and in vivo. Its overexpression in dividing cells (MCF7, PC12) protected against hypoxia/glucose deprivation and H2O2-triggered apoptosis by dramatically reducing reactive oxygen species generation, while in non-dividing neuron-like PC12 cells it promoted apoptosis and increased sensitivity to ischemic injury and oxidative stress. Tetracycline-repressible promoter-driven overexpression, ROS measurement, cell viability assays, in vivo ischemic stroke model Molecular and cellular biology Medium 11884613
2005 RTP801/REDD1 and its paralog RTP801L/REDD2 are stress-induced inhibitors of mTOR signaling. Both proteins work downstream of AKT and upstream of TSC2 to inhibit mTOR-dependent phosphorylation of S6K and 4EBP1. Overexpression, siRNA knockdown, phosphorylation assays of mTOR substrates (S6K, 4EBP1), epistasis placing REDD1 downstream of AKT and upstream of TSC2 The Journal of biological chemistry High 15632201
2005 REDD1 inhibits mTOR signaling through the TSC1/TSC2 complex. REDD1 is essential for mTOR regulation in response to hypoxia and energy stress; cells lacking REDD1 exhibit defective mTOR regulation under these stress signals. Genetic knockout/knockdown, TSC1/2 epistasis, cell size measurements in Drosophila and mammalian cells Cell cycle (Georgetown, Tex.) High 16258273
2006 RTP801 protein is elevated in dopaminergic neurons of the substantia nigra in Parkinson's disease. RTP801 overexpression is sufficient to promote neuronal death; its knockdown via shRNA is neuroprotective in cellular PD models. The mechanism involves repression of mTOR kinase activity, and death is inhibited by shRNAs targeting TSC2, a protein with which RTP801 interacts. Immunohistochemistry on postmortem PD brains, shRNA knockdown, overexpression in PC12 cells, co-immunoprecipitation with TSC2, mTOR activity assays The Journal of neuroscience High 17005863
2008 RTP801 mediates neuron death in Parkinson's disease models by suppressing mTOR signaling, which in turn reduces phosphorylation and activation of Akt. This sequential mechanism (stress → RTP801 → mTOR inhibition → Akt dephosphorylation → neuronal death) was validated by finding depletion of phospho-Akt (but not total Akt) in postmortem dopaminergic neurons from PD patients. shRNA knockdown of RTP801, 6-OHDA treatment, phospho-Akt measurements, postmortem PD brain immunohistochemistry The Journal of neuroscience High 19118169
2010 Rtp801/REDD1 inhibits mTOR by stabilizing the TSC1-TSC2 inhibitory complex and enhances oxidative stress-dependent cell death. In cigarette smoke-induced lung injury, Rtp801 is both necessary and sufficient for NF-κB activation; Rtp801 knockout mice are protected against acute cigarette smoke-induced lung injury and emphysema, partly via increased mTOR signaling. Rtp801 knockout mice, cigarette smoke exposure model, NF-κB reporter assays, forced lung expression of Rtp801 plasmid, mTOR signaling readouts Nature medicine High 20473305
2011 Glucocorticoid-induced elevation of Dig2/RTP801/REDD1 contributes to autophagy induction in lymphocytes by inhibiting mTOR signaling. RNAi-mediated suppression of REDD1 reduces both mTOR inhibition and autophagy in glucocorticoid-treated lymphocytes, and REDD1 knockout thymocytes show similar effects. REDD1-mediated autophagy promotes cell survival under glucocorticoid stress. RNAi knockdown, Rtp801/Redd1 knockout murine thymocytes, autophagy quantification, mTOR activity assays The Journal of biological chemistry High 21733849
2011 RTP801/REDD1 regulates the timing of cortical neurogenesis and neuron migration. RTP801 levels are high in embryonic cortical neuroprogenitors and diminished in newborn neurons. In vivo and in vitro knockdown of RTP801 accelerates cell cycle exit and neuronal differentiation, and disrupts migration of newborn neurons to the cortical plate, causing ectopic localization of mature neurons. In utero electroporation-based shRNA knockdown, in vitro RTP801 overexpression/knockdown, BrdU labeling, immunohistochemistry The Journal of neuroscience High 21368030
2004 The hypoxia-inducible transcription of the RTP801 promoter is mediated by an Sp1 binding site in the region between -495 and -446 bp. Co-transfection with antisense Sp1 oligonucleotides reduced hypoxia-induced RTP801 promoter activity. Promoter deletion and mutation analysis, luciferase reporter assays, antisense Sp1 co-transfection Pharmaceutical research Medium 15180327
2005 Arsenite induces RTP801 transcription through reactive oxygen species, and the transcription factors Elk-1 and C/EBP acting on an arsenic-responsive region between -1057 and -981 bp of the RTP801 promoter. The ERK pathway is partly responsible, and overexpression of Elk-1 and C/EBPβ elevates promoter activity. Promoter deletion/point mutation analysis, luciferase reporter assays, gel mobility-shift assays, antioxidant co-treatment, ERK inhibitor treatment The Biochemical journal Medium 16008523
2005 DNA damaging agent MMS induces RTP801 transcription through Elk-1 and C/EBPβ binding to a critical region between -1057 and -981 bp of the RTP801 promoter in human keratinocytes. Promoter deletion/mutation analysis, luciferase reporter assays, gel mobility-shift assay, anti-C/EBPβ supershift Biochemistry Medium 15751966
2009 Insulin stimulates REDD1 expression in adipocytes through a phosphoinositide 3-kinase/mTOR-dependent pathway that requires HIF-1α as the transcription factor mediating REDD1 induction. Insulin stimulation of murine and human adipocytes, PI3K inhibitor treatment, HIF-1 inhibitor (echinomycin), HIF-1α siRNA knockdown The Journal of biological chemistry Medium 19996311
2013 DDIT4/RTP801/REDD1 is expressed in Schwann cells and functions as a sustained negative regulator of PNS myelination. Loss of DDIT4 in Ddit4-null mice results in hypermyelination and enhanced mTORC1 activation in peripheral nerves, demonstrating that DDIT4 inhibits myelination via mTORC1. Ddit4-null mice, in vitro Schwann cell cultures, immunohistochemistry, electron microscopy for myelin thickness, mTORC1 phosphorylation assays The Journal of neuroscience High 24048858
2013 mTORC1 regulates REDD1 protein stability in a 26S proteasome-dependent manner; inhibition of mTORC1 reduces REDD1 protein stability and expression, while activation of mTORC1 increases REDD1 protein levels, establishing a novel mTORC1-REDD1 feedback loop. REDD1 degradation is not regulated by HUWE1, Cul4a, or other Cullin E3 ubiquitin ligases. mTORC1 inhibitors/activators, cycloheximide chase, proteasome inhibitors, siRNA knockdown of individual E3 ligases PloS one Medium 23717519
2013 REDD1 undergoes plasma membrane translocation triggered by GPCRs through a Ca2+/calmodulin pathway. REDD1's N-terminus and its conserved mTORC1-inhibitory motif are required for this dynamic plasma membrane interaction. Overexpression of REDD1 reduces GPCR-mediated mTORC1 activation, while depletion of endogenous REDD1 unleashes mTORC1 activity, identifying plasma membrane translocation as an inactivation mechanism for REDD1. Bioluminescent resonance energy transfer (BRET)-based plasma membrane localization assay, fluorescent live-imaging, siRNA knockdown, Ca2+/calmodulin pathway inhibitors Journal of cell science Medium 24338366
2014 Parkin E3 ligase physically interacts with RTP801 and promotes its poly-ubiquitination and proteasomal degradation. Parkin knockdown elevates RTP801 in neurons; ectopic parkin protects neuronal cells from RTP801-overexpression-induced death by mediating RTP801 degradation. RTP801 is elevated in parkin knockout mouse brains and human fibroblasts from AR-JP patients. Reciprocal co-immunoprecipitation, parkin knockdown/overexpression, ubiquitination assays, parkin knockout mouse brains, human AR-JP patient fibroblasts and postmortem PD brain immunohistochemistry Cell death & disease High 25101677
2014 REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy in vivo. REDD1-mediated mTORC1 inhibition in skeletal muscle after glucocorticoid treatment is not related to modulation of TSC2/14-3-3 binding but instead involves a mechanism linking REDD1, Akt, and PRAS40. REDD1-null mice, dexamethasone gavage, muscle weight and fiber size measurements, protein synthesis assays, mTORC1 target phosphorylation (S6, 4E-BP1, ULK1), co-immunoprecipitation for TSC2/14-3-3 American journal of physiology. Endocrinology and metabolism High 25315696
2016 NEDD4 E3 ligase polyubiquitinates RTP801 with K63-linked ubiquitin chains and targets it for degradation. NEDD4 and RTP801 interact physically in cells and in a cell-free system. NEDD4 loss of function (as occurs with neurotoxin 6-OHDA treatment) elevates RTP801, and NEDD4 knockdown toxicity in primary cortical neurons is mediated by RTP801 (double knockdown of NEDD4+RTP801 is neuroprotective). Cell-free ubiquitination assay, co-immunoprecipitation, ubiquitin-linkage specificity assays, shRNA knockdown, primary cortical neurons Oncotarget High 27494837
2017 REDD-1 promotes NF-κB activation through an atypical IKK-independent mechanism: REDD-1's C-terminal region (amino acids 178-229) interacts with and sequesters IκBα from the NF-κB/IκBα complex, enabling NF-κB activation during the delayed and persistent phases of inflammation. REDD-1 overexpression stimulates NF-κB-dependent inflammation without additional LPS stimulation. Co-immunoprecipitation of REDD-1 with IκBα, C-terminal domain mapping, REDD-1 knockdown/knockout macrophages, NF-κB reporter assays, endotoxemia mouse model FASEB journal High 29547704
2018 REDD1/autophagy pathway promotes NETosis in SLE neutrophils. NETosis correlates with increased REDD1 expression, and endothelin-1 (ET-1) and HIF-1α are key mediators of REDD1-driven NET release, as demonstrated by inhibition with bosentan and L-ascorbic acid respectively. Immunofluorescence, immunoblotting, NET quantification, pharmacological inhibition (bosentan, L-ascorbic acid, hydroxychloroquine), primary neutrophil cultures Annals of the rheumatic diseases Medium 30563869
2019 REDD1 activates a ROS-generating feedback loop in the diabetic retina. Hyperglycemia increases REDD1 expression and ROS. ROS in turn increases REDD1 (antioxidant NAC prevents REDD1 induction). REDD1 attenuates Akt/GSK3 phosphorylation in a REDD1-dependent manner, and in REDD1-deficient cells, dominant-negative Akt or constitutively active GSK3 restores ROS and mitochondrial dysfunction. REDD1-deficient mice, streptozotocin-induced diabetes, NAC antioxidant treatment, H2O2 exogenous ROS, dominant-negative Akt overexpression, constitutively active GSK3β, ROS assays Investigative ophthalmology & visual science Medium 31141608
2020 DDIT4 is expressed in normal gastric chief cells and suppresses mTORC1 during the initial phase of paligenosis (injury-induced metaplasia). Loss of DDIT4 leads to constitutively high mTORC1, causing mitotic entry of cells harboring DNA damage and increased spontaneous tumorigenesis in mice after multiple rounds of paligenosis. DDIT4-deficient mice, CRISPR/Cas9 DDIT4-/- human gastric cells, tamoxifen/MNU mouse models, 5-FU treatment, xenografts, proliferation and DNA damage markers Gastroenterology High 32956680
2021 DDIT4 S-nitrosylation at specific residues promotes assembly of the p38-MAPK signaling complex, driving hepatic ROS production. DDIT4 is a direct transcriptional target of the chromatin remodeler BRG1. S-nitrosylation-deficient DDIT4 fails to restore ROS production; compounds that influence DDIT4 S-nitrosylation (imatinib, nilotinib, nateglinide) attenuate p38-MAPK signaling and liver injury. BRG1 knockout, DDIT4 overexpression/knockdown, S-nitrosylation assays, molecular docking, in vitro and in vivo liver injury models, human liver biopsy correlation Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 34310076
2021 p53 activates DDIT4 expression indirectly through the transcription factor RFX7. DDIT4 is required for p53 to inhibit mTORC2-dependent AKT activation and for RFX7 to inhibit mTORC1. Under physiological nutrient conditions, basal p53-RFX7-DDIT4 activity constrains mTORC1. siRNA knockdown of DDIT4 and RFX7, p53 activation, mTORC1/mTORC2 substrate phosphorylation assays, physiological cell culture media Oncogene Medium 34907345
2021 ATF4-dependent REDD1 and Sestrin2 expression in response to metformin is required for mTORC1 inhibition, independent of AMPK activation. siRNA knockdown of REDD1 or Sestrin2 reverses metformin-induced mTORC1 inhibition. siRNA knockdown of REDD1 and Sestrin2, western blot for mTORC1 substrates, AMPK inhibitor treatment BMC cancer Medium 34253170
2022 REDD1 promotes NF-κB activation in diabetic retina by sustaining IκB kinase complex (IKK) autophosphorylation and K63-ubiquitination, leading to IκB degradation and NF-κB activation. REDD1 deletion promotes IκB expression and reduces NF-κB DNA-binding activity. REDD1 acts upstream of IκB by enhancing IKK complex autophosphorylation and K63-ubiquitination. REDD1 knockout cells and STZ-diabetic mice, IKK autophosphorylation and K63-ubiquitination assays, IκB expression, NF-κB DNA-binding (EMSA), macrophage infiltration quantification The Journal of biological chemistry High 36309088
2022 Hyperglycemic conditions promote a redox-sensitive C150/C157 disulfide bond in REDD1 that inhibits its lysosomal proteolysis via chaperone-mediated autophagy (CMA). REDD1 acetylation at K129 is required for recognition by the cytosolic chaperone HSC70 and CMA degradation. Formation of the C150/C157 disulfide bond causes allosteric disruption of a REDD1 degron, blocking CMA and stabilizing REDD1 protein. Discrete molecular dynamics simulations, site-directed mutagenesis (C150A/C157A and K129), disulfide bond assays, cycloheximide chase, proteasome/lysosome inhibitors, HSC70 co-immunoprecipitation Diabetes High 36170669
2022 REDD1 promotes obesity-induced metabolic inflammation via atypical IKK-independent NF-κB activation by sequestering IκBα from the NF-κB/IκBα complex. Lys219/220 residues of REDD1 are critical for IκBα binding; Lys219/220Ala REDD1 mutant cannot stimulate NF-κB, adipogenesis, or inflammation. Redd1-deficient adipose-derived stem cells lose potential to differentiate into adipocytes, while REDD1 overexpression stimulates preadipocyte differentiation. Whole-body and adipocyte-specific Redd1 knockout mice, REDD1 Lys219/220Ala knock-in mice, Co-IP for IκBα, NF-κB reporter assays, adipogenesis assays Nature communications High 36272977
2022 Müller glia-specific REDD1 knockout (REDD1-mgKO) mice do not develop diabetes-induced retinal REDD1 upregulation, oxidative stress, gliosis (GFAP), retinal thinning, neurodegeneration, or visual dysfunction. REDD1 in Müller glia is required for the failed adaptive retinal response in diabetes; the gliosis-prevention effect requires the antioxidant transcription factor Nrf2. Cell-type specific Cre-mediated REDD1 knockout, STZ-induced diabetes, immunohistochemistry, ROS assays, optometry, Nrf2 inhibition Diabetes High 35167652
2023 REDD1 promotes diabetes-induced retinal inflammation by promoting GSK3β dephosphorylation at S9 (activation of GSK3β). REDD1 deletion prevents GSK3β dephosphorylation; constitutively active GSK3β restores NF-κB activation in REDD1-deficient cells. GSK3β acts upstream of IKK autophosphorylation and IκB degradation to promote NF-κB signaling and macrophage infiltration. REDD1 knockout cells and STZ-diabetic mice, constitutively active GSK3β overexpression, GSK3 inhibitor treatment, phospho-GSK3β and IKK assays, macrophage infiltration quantification The Journal of biological chemistry High 37392853
2024 Disrupted methionine cycle in cancer cachexia leads to DNA hypomethylation of the DDIT4/Redd1 promoter, enabling ATF4-mediated transcriptional upregulation of DDIT4. DNMT3A methylates the Ddit4 promoter; DNMT3A depletion exacerbates cachexia while REDD1 knockout alleviates it. Methionine supplementation restores DNMT3A-dependent DNA methylation of the Ddit4 promoter and inhibits ATF4-mediated Ddit4 transcription. DNMT3A knockout/overexpression, REDD1 knockout mice, methionine supplementation, chromatin immunoprecipitation, DNA methylation assays, cancer cachexia mouse models Cell metabolism High 39729999
2015 The transcription factor TAL1/SCL directly represses DDIT4/REDD1 expression in human hematopoietic stem/progenitor cells (HSPCs). TAL1 knockdown increases DDIT4 and reduces mTOR pathway activity; chromatin immunoprecipitation confirmed direct TAL1 binding to the DDiT4 gene. DDIT4 upregulation by TAL1 knockdown reduces HSPC proliferation. TAL1 knockdown and overexpression, chromatin immunoprecipitation (ChIP) in human HSPCs, gene expression microarrays, mTOR substrate phosphorylation Stem cells (Dayton, Ohio) Medium 25858676
2006 scylla and charybde, Drosophila homologues of RTP801/DDIT4, are required for embryonic head involution. Both gene products are transcriptionally regulated targets of Dpp/Zen-mediated signal transduction and downstream of homeobox regulation. Gene disruption in Drosophila, in situ hybridization expression screen, genetic epistasis with dpp/zen signaling Developmental biology Medium 16423342
2021 REDD1 promotes cardiomyocyte senescence as a downstream effector of p38 MAPK signaling, promoting NF-κB signaling via p65 phosphorylation and nuclear translocation. Redd1 overexpression accentuates doxorubicin-induced senescence, while AAV9-shRNA-mediated Redd1 silencing alleviates cardiac dysfunction. AAV9-shRNA knockdown, lentiviral overexpression, p38 MAPK pharmacological inhibition, immunofluorescence, western blotting, in vitro and in vivo doxorubicin models Aging Medium 33962393
2022 PERK/ATF4 signaling axis is required for REDD1 induction in cardiomyocytes under hyperglycemic/hyperlipidemic conditions. REDD1 deletion reduces proinflammatory cytokine expression (IL-1β, IL-6, TNFα) in cardiomyocytes and in hearts of obese mice. Pharmacological PERK inhibition or ATF4 knockdown prevents the REDD1 increase. PERK inhibitor, ATF4 siRNA knockdown, REDD1 knockout cardiomyocytes and mice, high-fat high-sucrose diet model, cytokine expression assays American journal of physiology. Endocrinology and metabolism Medium 36383638
2021 REDD1 mediates motor-learning dysfunction in Huntington's disease by affecting striatal synaptic plasticity. Mhtt-induced RTP801 is elevated in synapses of cultured neurons, HD patient striata, and mouse models. AAV-shRNA knockdown of striatal RTP801 in R6/1 mice prevents motor-learning impairment, normalizes Ser473 Akt hyperphosphorylation by downregulating Rictor, and induces synaptic elevation of GluA1 and TrkB. AAV-shRNA striatal knockdown in R6/1 mice, synaptosomal fractionation, western blot, motor learning tests, human postmortem HD brain samples Cell death & disease High 32732871
2021 RTP801/REDD1 contributes to neuroinflammation and memory impairments in Alzheimer's disease. RTP801 levels in hippocampus correlate with Braak and Thal staging and with GFAP expression. AAV-shRNA knockdown of RTP801 in 5xFAD mouse hippocampal neurons ameliorates cognitive deficits and recovers gliosis hallmarks and inflammasome key proteins. AAV-shRNA hippocampal knockdown in 5xFAD mice, postmortem human AD hippocampal samples, cognitive tests, GFAP and inflammasome protein quantification Cell death & disease High 34131105
2018 REDD1 inhibits mTORC1 by activating the TSC1/2 complex and confers therapy resistance in glioblastoma. DDIT4 gene suppression sensitizes glioma cells to hypoxia-induced cell death and to temozolomide and radiotherapy, while DDIT4 induction (via doxycycline-regulated system) confers protection from these treatments. An intact DDIT4-mTORC1 signaling axis was demonstrated in human glioblastoma cells. shRNA-mediated DDIT4 suppression, doxycycline-inducible DDIT4 overexpression, clonogenic survival assays, mTORC1 signaling readouts, hypoxia treatment British journal of cancer Medium 30745581
2016 REDD1 is involved in inflammation independently of mTORC1 activation. Loss of REDD1 decreases proinflammatory cytokine expression and inhibits p38MAPK, JNK, NF-κB, and NLRP3 inflammasome activation in macrophages, reducing IL-1β secretion. This anti-inflammatory effect of REDD1 deletion is associated with decreased ROS through dysregulation of Nox-1 and GPx3, implicating oxidative stress rather than mTORC1 in this context. REDD1-/- bone marrow-derived macrophages, LPS/ATP stimulation, REDD1-/- mice, cytokine ELISAs, NLRP3 inflammasome activation, ROS assays Scientific reports Medium 28765650
2025 Podocyte-specific REDD1 is required for NF-κB activation and chemokine expression under hyperglycemic conditions, contributing to macrophage chemotaxis and infiltration. REDD1 deletion in podocytes attenuates diabetic nephropathy markers including albuminuria and NLRP3-mediated caspase-1 activation (pyroptosis). REDD1 expression in podocytes is necessary for diabetes-induced pro-inflammatory immune cell infiltration in kidneys. Podocyte-specific REDD1 knockout mice, STZ-induced diabetes, NF-κB activity assays, NLRP3/caspase-1 assays, macrophage chemotaxis assays, LDH release Cell death & disease High 39920111

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Molecular and cellular biology 493 11884613
2018 REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Annals of the rheumatic diseases 223 30563869
2010 Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nature medicine 199 20473305
2005 The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. The Journal of biological chemistry 198 15632201
2008 RTP801 is induced in Parkinson's disease and mediates neuron death by inhibiting Akt phosphorylation/activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 194 19118169
2006 RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. The Journal of neuroscience : the official journal of the Society for Neuroscience 153 17005863
2003 Dexamethasone-induced gene 2 (dig2) is a novel pro-survival stress gene induced rapidly by diverse apoptotic signals. The Journal of biological chemistry 131 12736248
1998 Differential regulation of transcription: repression by unactivated mitogen-activated protein kinase Kss1 requires the Dig1 and Dig2 proteins. Proceedings of the National Academy of Sciences of the United States of America 124 9860980
2004 Inhibition of oxygen-induced retinopathy in RTP801-deficient mice. Investigative ophthalmology & visual science 108 15452091
2005 Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell cycle (Georgetown, Tex.) 107 16258273
2014 REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy. American journal of physiology. Endocrinology and metabolism 89 25315696
2018 DDIT4 promotes gastric cancer proliferation and tumorigenesis through the p53 and MAPK pathways. Cancer communications (London, England) 86 29976242
2011 Neuroprotective effect of ligustilide against ischaemia-reperfusion injury via up-regulation of erythropoietin and down-regulation of RTP801. British journal of pharmacology 83 21410687
2022 The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway. Molecular cancer 79 36056355
2011 Glucocorticoid elevation of dexamethasone-induced gene 2 (Dig2/RTP801/REDD1) protein mediates autophagy in lymphocytes. The Journal of biological chemistry 78 21733849
2014 Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells. Cancer letters 77 25543165
2020 DDIT4 Licenses Only Healthy Cells to Proliferate During Injury-induced Metaplasia. Gastroenterology 74 32956680
2016 Effects of DDIT4 in Methamphetamine-Induced Autophagy and Apoptosis in Dopaminergic Neurons. Molecular neurobiology 73 26873849
2023 Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 72 37096846
2017 Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy. Clinical cancer research : an official journal of the American Association for Cancer Research 65 29084921
2019 The physiological mTOR complex 1 inhibitor DDIT4 mediates therapy resistance in glioblastoma. British journal of cancer 64 30745581
2003 Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: involvement of RTP801 in amyloid beta-peptide toxicity. Experimental & molecular medicine 61 14646594
2020 Is REDD1 a metabolic double agent? Lessons from physiology and pathology. American journal of physiology. Cell physiology 58 32877205
2005 Arsenite induces a cell stress-response gene, RTP801, through reactive oxygen species and transcription factors Elk-1 and CCAAT/enhancer-binding protein. The Biochemical journal 58 16008523
2012 Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients. Eye (London, England) 57 22627477
2009 Insulin induces REDD1 expression through hypoxia-inducible factor 1 activation in adipocytes. The Journal of biological chemistry 56 19996311
2018 DDIT4 and Associated lncDDIT4 Modulate Th17 Differentiation through the DDIT4/TSC/mTOR Pathway. Journal of immunology (Baltimore, Md. : 1950) 55 29378913
2016 Is REDD1 a Metabolic Éminence Grise? Trends in endocrinology and metabolism: TEM 54 27613400
2017 Implication of REDD1 in the activation of inflammatory pathways. Scientific reports 53 28765650
2011 RTP801/REDD1 regulates the timing of cortical neurogenesis and neuron migration. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 21368030
2016 DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes. Toxicology and applied pharmacology 52 26825372
2014 RTP801/REDD1: a stress coping regulator that turns into a troublemaker in neurodegenerative disorders. Frontiers in cellular neuroscience 52 25324725
2004 Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease. Pharmaceutical research 52 15180327
2019 Induction of DDIT4 Impairs Autophagy Through Oxidative Stress in Dry Eye. Investigative ophthalmology & visual science 49 31266058
2013 DDIT4/REDD1/RTP801 is a novel negative regulator of Schwann cell myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 24048858
2020 A Key Role of DNA Damage-Inducible Transcript 4 (DDIT4) Connects Autophagy and GLUT3-Mediated Stemness To Desensitize Temozolomide Efficacy in Glioblastomas. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 46 31916238
2023 The stress-responsive protein REDD1 and its pathophysiological functions. Experimental & molecular medicine 45 37653030
2021 lncRNA C2dat2 facilitates autophagy and apoptosis via the miR-30d-5p/DDIT4/mTOR axis in cerebral ischemia-reperfusion injury. Aging 45 33833132
2014 Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease. Cell death & disease 42 25101677
2021 A review of the mechanism of DDIT4 serve as a mitochondrial related protein in tumor regulation. Science progress 41 33729069
2016 Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism. American journal of physiology. Endocrinology and metabolism 40 27189933
2011 FLZ protects dopaminergic neuron through activating protein kinase B/mammalian target of rapamycin pathway and inhibiting RTP801 expression in Parkinson's disease models. Neuroscience 40 22138155
2021 RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer's disease. Cell death & disease 39 34131105
2024 Disrupted methionine cycle triggers muscle atrophy in cancer cachexia through epigenetic regulation of REDD1. Cell metabolism 36 39729999
2019 REDD1 Activates a ROS-Generating Feedback Loop in the Retina of Diabetic Mice. Investigative ophthalmology & visual science 36 31141608
2018 REDD-1 aggravates endotoxin-induced inflammation via atypical NF-κB activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 29547704
2021 LncRNA-MIAT promotes neural cell autophagy and apoptosis in ischemic stroke by up-regulating REDD1. Brain research 35 33745924
2021 DDIT4 S-Nitrosylation Aids p38-MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 35 34310076
2021 Redd1 knockdown prevents doxorubicin-induced cardiac senescence. Aging 34 33962393
2021 High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer. Scientific reports 34 34211002
2022 DHA alleviates diet-induced skeletal muscle fiber remodeling via FTO/m6A/DDIT4/PGC1α signaling. BMC biology 33 35135551
2014 REDD1 attenuates cardiac hypertrophy via enhancing autophagy. Biochemical and biophysical research communications 33 25450383
2013 mTORC1 dependent regulation of REDD1 protein stability. PloS one 33 23717519
2013 Plasma membrane translocation of REDD1 governed by GPCRs contributes to mTORC1 activation. Journal of cell science 31 24338366
2005 Induction of a cell stress response gene RTP801 by DNA damaging agent methyl methanesulfonate through CCAAT/enhancer binding protein. Biochemistry 31 15751966
2021 REDD1 attenuates hepatic stellate cell activation and liver fibrosis via inhibiting of TGF-β/Smad signaling pathway. Free radical biology & medicine 30 34614448
2021 Loss of REDD1 prevents chemotherapy-induced muscle atrophy and weakness in mice. Journal of cachexia, sarcopenia and muscle 30 34664403
2021 p53-mediated AKT and mTOR inhibition requires RFX7 and DDIT4 and depends on nutrient abundance. Oncogene 30 34907345
2024 The FTO Mediated N6-Methyladenosine Modification of DDIT4 Regulation with Tumorigenesis and Metastasis in Prostate Cancer. Research (Washington, D.C.) 29 38384328
2018 RTP801 is a critical factor in the neurodegeneration process of A53T α-synuclein in a mouse model of Parkinson's disease under chronic restraint stress. British journal of pharmacology 29 29130486
2015 REDD1 Is Essential for Optimal T Cell Proliferation and Survival. PloS one 29 26301899
2007 RTP801 is a novel retinoic acid-responsive gene associated with myeloid differentiation. Experimental hematology 29 17379067
2022 Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe? International journal of molecular sciences 28 36077083
2021 The stress response protein REDD1 as a causal factor for oxidative stress in diabetic retinopathy. Free radical biology & medicine 28 33524531
2016 DDIT4 regulates mesenchymal stem cell fate by mediating between HIF1α and mTOR signalling. Scientific reports 28 27876894
2018 Rapamycin Modulates Glucocorticoid Receptor Function, Blocks Atrophogene REDD1, and Protects Skin from Steroid Atrophy. The Journal of investigative dermatology 27 29596905
2018 Induction of REDD1 via AP-1 prevents oxidative stress-mediated injury in hepatocytes. Free radical biology & medicine 27 29909290
2023 Lipoteichoic acid restrains macrophage senescence via β-catenin/FOXO1/REDD1 pathway in age-related osteoporosis. Aging cell 26 38126583
2016 Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis. Proceedings of the National Academy of Sciences of the United States of America 26 27382160
2013 RTP801 immunoreactivity in retinal ganglion cells and its down-regulation in cultured cells protect them from light and cobalt chloride. Brain research bulletin 26 23978538
2022 Müller Glial Expression of REDD1 Is Required for Retinal Neurodegeneration and Visual Dysfunction in Diabetic Mice. Diabetes 25 35167652
2022 REDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation. Nature communications 25 36272977
2016 Loss of NEDD4 contributes to RTP801 elevation and neuron toxicity: implications for Parkinson's disease. Oncotarget 25 27494837
2014 REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes. Molecular cancer research : MCR 25 24615339
2012 RTP801 is required for ceramide-induced cell-specific death in the murine lung. American journal of respiratory cell and molecular biology 25 23024063
2006 Low glucocorticoid receptor (GR), high Dig2 and low Bcl-2 expression in double positive thymocytes of BALB/c mice indicates their endogenous glucocorticoid hormone exposure. Immunobiology 25 17113916
2021 An integrative transcriptome study reveals Ddit4/Redd1 as a key regulator of cancer cachexia in rodent models. Cell death & disease 24 34175899
2021 Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin. BMC cancer 24 34253170
2015 Acute Alcohol-Induced Decrease in Muscle Protein Synthesis in Female Mice Is REDD-1 and mTOR-Independent. Alcohol and alcoholism (Oxford, Oxfordshire) 24 26394774
2015 The SCL/TAL1 Transcription Factor Represses the Stress Protein DDiT4/REDD1 in Human Hematopoietic Stem/Progenitor Cells. Stem cells (Dayton, Ohio) 23 25858676
2022 DDIT4 promotes malignancy of head and neck squamous cell carcinoma. Molecular carcinogenesis 22 36453700
2023 Role of Autophagy Mediated by AMPK/DDiT4/mTOR Axis in HT22 Cells Under Oxygen and Glucose Deprivation/Reoxygenation. ACS omega 21 36936290
2022 PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice. American journal of physiology. Endocrinology and metabolism 20 36383638
2021 REDD1 deletion attenuates cancer cachexia in mice. Journal of applied physiology (Bethesda, Md. : 1985) 20 34672766
2020 REDD1 deficiency protects against nonalcoholic hepatic steatosis induced by high-fat diet. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 32043636
2015 RTP801 Is Involved in Mutant Huntingtin-Induced Cell Death. Molecular neurobiology 20 25876513
2014 Changes and expressions of Redd1 in neurons and glial cells in the gerbil hippocampus proper following transient global cerebral ischemia. Journal of the neurological sciences 20 24980938
2012 Retina expression and cross-species validation of gene silencing by PF-655, a small interfering RNA against RTP801 for the treatment of ocular disease. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 20 22304497
2007 The pheromone-induced nuclear accumulation of the Fus3 MAPK in yeast depends on its phosphorylation state and on Dig1 and Dig2. BMC cell biology 20 17963515
2024 siRNA incorporated in slow-release injectable hydrogel continuously silences DDIT4 and regulates nucleus pulposus cell pyroptosis through the ROS/TXNIP/NLRP3 axis to alleviate intervertebral disc degeneration. Bone & joint research 19 38771134
2025 REDD1 expression in podocytes facilitates renal inflammation and pyroptosis in streptozotocin-induced diabetic nephropathy. Cell death & disease 18 39920111
2022 Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts. Aging 18 35680564
2022 Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions. Diabetes 18 36170669
2022 Downregulation of DDIT4 ameliorates abnormal behaviors in autism by inhibiting ferroptosis via the PI3K/Akt pathway. Biochemical and biophysical research communications 18 36528956
2023 Resveratrol improves palmitic acid‑induced insulin resistance via the DDIT4/mTOR pathway in C2C12 cells. Molecular medicine reports 17 37594055
2022 Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling. The Journal of biological chemistry 17 36309088
2021 Overexpression of DDIT4 and TPTEP1 are associated with metastasis and advanced stages in colorectal cancer patients: a study utilizing bioinformatics prediction and experimental validation. Cancer cell international 17 34107956
2023 REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice. The Journal of biological chemistry 16 37392853
2020 Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease. Cell death & disease 16 32732871
2006 scylla and charybde, homologues of the human apoptotic gene RTP801, are required for head involution in Drosophila. Developmental biology 16 16423342

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