DDIT4

Summary

DDIT4 (DNA damage inducible transcript 4, HGNC:24944) is a protein-coding gene on chromosome 10q22.1, encoding DNA damage-inducible transcript 4 protein (Q9NX09). Regulates cell growth, proliferation and survival via inhibition of the activity of the mammalian target of rapamycin complex 1 (mTORC1).

Predicted to enable 14-3-3 protein binding activity. Involved in negative regulation of TOR signaling and response to hypoxia. Located in cytosol.

Source: NCBI Gene 54541 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_019058

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24944
Approved symbol	DDIT4
Name	DNA damage inducible transcript 4
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	RTP801, FLJ20500, REDD-1, REDD1, Dig2
Ensembl gene	ENSG00000168209
Ensembl biotype	protein_coding
OMIM	607729
Entrez	54541

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000307365, ENST00000471240, ENST00000473155, ENST00000491934, ENST00000681898, ENST00000871236

RefSeq mRNA: 1 — MANE Select: NM_019058 NM_019058

CCDS: CCDS7315

Canonical transcript exons

ENST00000307365 — 3 exons

Exon	Start	End
ENSE00001170374	72274695	72276036
ENSE00001170385	72274157	72274421
ENSE00001459505	72273924	72274060

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.9113 / max 899.9138, expressed in 1779 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105488	46.6785	1765
105489	1.8929	904
205897	1.3399	673

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	99.83	gold quality
lower esophagus mucosa	UBERON:0035834	99.60	gold quality
right ovary	UBERON:0002118	99.44	gold quality
vena cava	UBERON:0004087	99.37	gold quality
left ovary	UBERON:0002119	99.34	gold quality
nerve	UBERON:0001021	99.26	gold quality
tibial nerve	UBERON:0001323	99.26	gold quality
pharyngeal mucosa	UBERON:0000355	99.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.10	gold quality
vagina	UBERON:0000996	99.06	gold quality
body of pancreas	UBERON:0001150	98.91	gold quality
trachea	UBERON:0003126	98.81	gold quality
ectocervix	UBERON:0012249	98.80	gold quality
right adrenal gland	UBERON:0001233	98.79	gold quality
esophagus mucosa	UBERON:0002469	98.78	gold quality
right lung	UBERON:0002167	98.77	gold quality
adrenal cortex	UBERON:0001235	98.75	gold quality
right adrenal gland cortex	UBERON:0035827	98.75	gold quality
left adrenal gland	UBERON:0001234	98.72	gold quality
trigeminal ganglion	UBERON:0001675	98.72	gold quality
left adrenal gland cortex	UBERON:0035825	98.72	gold quality
type B pancreatic cell	CL:0000169	98.65	gold quality
seminal vesicle	UBERON:0000998	98.62	gold quality
tibial artery	UBERON:0007610	98.55	gold quality
popliteal artery	UBERON:0002250	98.53	gold quality
olfactory bulb	UBERON:0002264	98.53	gold quality
dorsal root ganglion	UBERON:0000044	98.40	gold quality
ovary	UBERON:0000992	98.34	gold quality
left uterine tube	UBERON:0001303	98.27	gold quality
adenohypophysis	UBERON:0002196	98.27	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-MTAB-6108	yes	8918.87
E-MTAB-8142	yes	4013.05
E-MTAB-11121	yes	1132.64
E-HCAD-23	yes	959.52
E-MTAB-3929	yes	607.31
E-MTAB-9154	yes	482.07
E-MTAB-8498	yes	286.34
E-MTAB-6701	yes	126.48
E-HCAD-4	yes	48.19
E-CURD-122	yes	45.64
E-CURD-88	yes	34.91
E-MTAB-6678	yes	24.59
E-MTAB-7316	yes	23.47
E-HCAD-1	yes	23.42
E-HCAD-25	yes	22.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, CEBPB, CEBPE, CEBPG, E2F1, ELK1, ESR1, HIF1A, NFATC3, SP1, TP53, VDR

miRNA regulators (miRDB)

99 targeting DDIT4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• RTP801 might play important roles in Abeta toxicity and the pathogenesis of Alzheimer’s disease (PMID:14646594)
• co-transfection with antisense Sp1 oligonucleotide suggests that hypoxia induction of the RTP801 promoter is mediated by Sp1 (PMID:15180327)
• REDD1 (RTP801) can act as a transcriptional downstream target of PI 3-kinase signaling in human prostate cancer cells. (PMID:15592522)
• RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions (PMID:15632201)
• REDD1 as a critical transducer of the cellular response to energy depletion through the TSC-mTOR pathway. (PMID:15988001)
• Stress response gene REDD1 is identified in this review as an essential regulator of checkpoint kinase mTOR activity through the tuberous sclerosis tumor suppressors TSC1/2 complex. (PMID:16258273)
• The elevation of RTP801 we detect in PD substantia nigral neurons may mediate their degeneration. (PMID:17005863)
• These results demonstrate that hypoxic condition-and high cell density-induced expression of Redd1 is mediated by coactivation of Sp1 and HIF-1alpha downstream of the PI3K/Akt signaling pathway. (PMID:17307335)
• unique effect of inhibition of fatty-acid synthase results from negative regulation of the mTOR pathway via DDIT4 (PMID:18796435)
• results suggest a novel mechanism by which AMPK activation after hypoxia-induced energy stress may be crucial in regulating REDD1 expression to control the mTOR pathway in head and neck squamous cell carcinoma (PMID:18953439)
• The results suggest that REDD1 expression is upregulated during ER stress through a mechanism involving activation of PERK, phosphorylation of eIF2alpha, and increased ATF4 expression. (PMID:19114033)
• REDD1 expression in response to hypoxia and dexamethasone is cell-type specific and that physiologically appropriate levels of PO2 should be used when investigating fetal lung development. (PMID:19127203)
• PKR represents a cognitive decline biomarker able to dysregulate translation via two consecutive targets p53 and Redd1 in Alzheimer disease lymphocytes (PMID:19210572)
• DNA-damage-inducible transcript 4 is a key mediator in RAS protein -mediated transformation through an effect on anti-apoptosis. (PMID:19221489)
• REDD1 degradation is crucially required for the restoration of mTOR signalling as cells recover from hypoxic stress. (PMID:19557001)
• Insulin induces REDD1 expression through hypoxia-inducible factor 1 activation in adipocytes. (PMID:19996311)
• Structure/function analyses have led us to identify two segments in REDD1 that are essential for mTORC1 inhibition. (PMID:20166753)
• sertraline exerts antiproliferative activity by targeting the mTOR signaling pathway in a REDD1-dependent manner (PMID:20354178)
• that expression of RTP801 was lower in oral lichen planus than in controls (PMID:20374513)
• Our data support the notion that Rtp801 may represent a major molecular sensor and mediator of cigarette smoke-induced lung injury. (PMID:20473305)
• DDIT4, an inhibitor of mTOR signaling, is a direct target for 1,25(OH)(2)D(3) and VDRE-BP, and functions to suppress cell proliferation in response to vitamin D (PMID:21123297)
• Data show that miR-495 expression was directly modulated by transcription factor E12/E47, and promotes oncogenesis via downregulation of E-cadherin and REDD1. (PMID:21258409)
• In the HER2 overexpression type and triple-negative breast carcer, tumor cell proliferation and survival in the hypoxic tumor environment could possibly be due to disinhibition of the mTOR pathway and HIF-1alpha stabilization by downregulation of REDD1. (PMID:21266827)
• these results provide preliminary evidence that Redd1 inhibits the invasive activity of NSCLC cells via suppression of the mTOR downstream pathway. (PMID:21414293)
• these results collectively demonstrate that TXNIP stabilizes Redd1 protein induced by ATF4 in response to 2-DG, resulting in potentiation of mTOR suppression. (PMID:21460850)
• Metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. (PMID:21540236)
• mechanisms have evolved in tumors to escape growth suppressive signals resulting from VHL loss and REDD1 upregulation (PMID:21798997)
• REDD1 is a new host defense factor, and chemical activation of REDD1 expression represents a potent antiviral intervention strategy (PMID:21909097)
• REDD1 expression plays a role in maintaining normal function of placenta, while the increase of REDD1 is related to the pathogenesis of pre-eclampsia. (PMID:22527987)
• An immobilization-induced attenuation of mTORC1 signaling mediated by induction of REDD1/2 and defective p70S6K1 phosphorylation. (PMID:23193052)
• The sustained overexpression of Redd1 leads to mTORC1 inhibition and to consequent Akt activation that is involved in cell survival. (PMID:23528835)
• mTORC1 regulates REDD1 protein stability in a 26S proteasome dependent manner. (PMID:23717519)
• Translocation to the plasma membrane appears to be an inactivation mechanism of REDD1 by G-protein coupled receptors. (PMID:24338366)
• these postmortem and preclinical findings identify REDD1 as a critical mediator of the atrophy of neurons and depressive behavior caused by chronic stress exposure (PMID:24728411)
• the results demonstrate that REDD1 acts not only as a repressor of mTORC1 but also as a constant modulator of the phosphorylation of Akt in response to growth factors and nutrients. (PMID:25056877)
• Caspase 3 cleaved REDD1 during apoptotic activation. (PMID:25058423)
• analysis of ubiquitin-mediated proteolysis of DNA damage-inducible transcript 4 (DDIT4) by the E3 ligase HUWE1 (PMID:25147182)
• MiR-630 reduced apoptosis by downregulating several apoptotic modulators, PARP3, DDIT4, and EP300. (PMID:25255219)
• REDD1 and p-AKT over-expression may serve as a prognostic biomarker in ovarian cancer, but KRAS mutations and REDD1 protein over-expression were not correlated in OC. (PMID:25337238)
• REDD1 knockout (KO) mice, all skin compartments, epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. (PMID:25504525)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddit4	ENSDARG00000037618
mus_musculus	Ddit4	ENSMUSG00000020108
rattus_norvegicus	Ddit4	ENSRNOG00000057078
drosophila_melanogaster	chrb	FBGN0036165
drosophila_melanogaster	scyl	FBGN0041094

Paralogs (1): DDIT4L (ENSG00000145358)

Protein

Protein identifiers

DNA damage-inducible transcript 4 protein — Q9NX09 (reviewed: Q9NX09)

Alternative names: HIF-1 responsive protein RTP801, Protein regulated in development and DNA damage response 1

All UniProt accessions (2): A0A7P0Z4M7, Q9NX09

UniProt curated annotations — full annotation on UniProt →

Function. Regulates cell growth, proliferation and survival via inhibition of the activity of the mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an important role in responses to cellular energy levels and cellular stress, including responses to hypoxia and DNA damage. Regulates p53/TP53-mediated apoptosis in response to DNA damage via its effect on mTORC1 activity. Its role in the response to hypoxia depends on the cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, but not in hepatocytes. Required for mTORC1-mediated defense against viral protein synthesis and virus replication. Inhibits neuronal differentiation and neurite outgrowth mediated by NGF via its effect on mTORC1 activity. Required for normal neuron migration during embryonic brain development. Plays a role in neuronal cell death.

Subunit / interactions. Monomer. Interacts with BTRC. Identified in a complex with CUL4A, DDB1 and BTRC. Interacts with TXNIP; this inhibits the proteasomal degradation of DDIT4.

Subcellular location. Mitochondrion. Cytoplasm. Cytosol.

Tissue specificity. Broadly expressed, with lowest levels in brain, skeletal muscle and intestine. Up-regulated in substantia nigra neurons from Parkinson disease patients (at protein level).

Post-translational modifications. Phosphorylated by GSK3B; this promotes proteasomal degradation. Polyubiquitinated by a DCX (DDB1-CUL4A-RBX1) E3 ubiquitin-protein ligase complex with BTRC as substrate-recognition component, leading to its proteasomal degradation.

Induction. Up-regulated in fibroblasts upon ionizing radiation, via a TP53-dependent pathway. Up-regulated by TP63 in primary keratinocytes, and down-regulated during keratinocyte differentiation. Up-regulated upon DNA alkylation. Up-regulated by amyloid beta-peptide and retinoic acid. Up-regulated by hypoxia, via a PI3K and HIF1A-dependent but TP53/TP63-independent mechanism (at protein level).

Similarity. Belongs to the DDIT4 family.

RefSeq proteins (1): NP_061931* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012918	RTP801-like	Family
IPR038281	RTP801-like_C_sf	Homologous_superfamily

Pfam: PF07809

UniProt features (28 total): mutagenesis site 11, strand 5, modified residue 4, helix 3, chain 1, region of interest 1, sequence conflict 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3LQ9	X-RAY DIFFRACTION	2
7MOP	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX09-F1	71.50	0.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 19, 23, 25, 121

Mutagenesis-validated functional residues (11):

Position	Phenotype
103	no effect on inhibition of mtorc1.
133	no effect on inhibition of mtorc1.
137	no effect on inhibition of mtorc1.
139	abolishes inhibition of mtorc1.
140	mildly reduces inhibition of mtorc1.
219	reduces inhibition of mtorc1. abolishes inhibition of mtorc1; when associated with a-222.
221	reduces inhibition of mtorc1.
222	reduces inhibition of mtorc1. abolishes inhibition of mtorc1; when associated with a-219.
19	strongly inhibits proteasomal degradation.
23	strongly inhibits proteasomal degradation. strongly inhibits proteasomal degradation; when associated with a-25.
25	strongly inhibits proteasomal degradation; when associated with a-23.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes

MSigDB gene sets: 559 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_BCELL_DN, MODULE_52, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, WANG_CLIM2_TARGETS_UP, MYOGENIN_Q6, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GCANCTGNY_MYOD_Q6, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, FOXO4_01, FOXO1_01

GO Biological Process (15): response to hypoxia (GO:0001666), neuron migration (GO:0001764), apoptotic process (GO:0006915), brain development (GO:0007420), neuron differentiation (GO:0030182), negative regulation of TOR signaling (GO:0032007), protein-containing complex disassembly (GO:0032984), intracellular signal transduction (GO:0035556), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), negative regulation of glycolytic process (GO:0045820), neurotrophin TRK receptor signaling pathway (GO:0048011), defense response to virus (GO:0051607), cellular response to dexamethasone stimulus (GO:0071549), reactive oxygen species metabolic process (GO:0072593), negative regulation of signal transduction (GO:0009968)

GO Molecular Function (2): 14-3-3 protein binding (GO:0071889), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transcriptional Regulation by TP53	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
generation of neurons	2
intracellular anatomical structure	2
signal transduction	2
cellular anatomical structure	2
cytoplasm	2
response to stress	1
response to decreased oxygen levels	1
cell migration	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
central nervous system development	1
animal organ development	1
head development	1
cell differentiation	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
cellular component disassembly	1
protein-containing complex organization	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
glycolytic process	1
regulation of glycolytic process	1
negative regulation of purine nucleotide catabolic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of ATP metabolic process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
neurotrophin signaling pathway	1
defense response	1
response to virus	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
metabolic process	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
protein binding	1

Protein interactions and networks

STRING

2128 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDIT4	TXNIP	Q9H3M7	989
DDIT4	TSC2	P49815	916
DDIT4	RPTOR	Q8N122	840
DDIT4	MTOR	P42345	800
DDIT4	RHEB	Q15382	742
DDIT4	AKT1	P31749	733
DDIT4	TSC1	Q92574	716
DDIT4	RICTOR	Q6R327	676
DDIT4	MLST8	Q9BVC4	668
DDIT4	RRAGB	Q5VZM2	661
DDIT4	RRAGC	Q9HB90	657
DDIT4	TP53	P04637	653
DDIT4	RRAGD	Q9NQL2	652
DDIT4	RRAGA	Q7L523	640
DDIT4	EIF4E	P06730	622

IntAct

53 interactions, top by confidence:

A	B	Type	Score
UBE2K	DDIT4	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	PECAM1	psi-mi:“MI:0915”(physical association)	0.560
PMF1	DDIT4	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	SLC3A2	psi-mi:“MI:0915”(physical association)	0.560
VHL	DDIT4	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	KEAP1	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	MTF2	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	KLF3	psi-mi:“MI:0915”(physical association)	0.560
DDIT4		psi-mi:“MI:0915”(physical association)	0.560
DDIT4	ZNF488	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	VSX2	psi-mi:“MI:0915”(physical association)	0.560
DDIT4	FOXD4L6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (34): DDIT4 (Affinity Capture-Western), DDIT4 (Reconstituted Complex), DDIT4 (Affinity Capture-Western), DDIT4 (Co-localization), DDIT4 (Affinity Capture-Western), HUWE1 (Affinity Capture-Western), DDIT4 (Affinity Capture-Western), DDIT4 (Two-hybrid), NEDD4 (Affinity Capture-Western), DDIT4 (Reconstituted Complex), DDIT4 (Proximity Label-MS), LRIF1 (Two-hybrid), DDIT4 (Affinity Capture-RNA), DDIT4 (Positive Genetic), DDIT4 (Affinity Capture-RNA)

ESM2 similar proteins: A6QQA5, A7YWU3, B5XBP5, F5HA27, F5HF47, F5HG20, O36381, O36391, O36416, O36417, P03185, P03220, P0C6Z9, P0C866, P0CK56, P0CK57, P10191, P20402, P29882, P78543, Q03552, Q04566, Q07G87, Q1RMA6, Q20A00, Q2HR98, Q3KSP4, Q3KSR8, Q3TDK6, Q4V7D2, Q567C3, Q5BK64, Q5PQ92, Q5R7X1, Q5REJ0, Q5U2R2, Q66669, Q6DFN5, Q758A1, Q7ZVT5

Diamond homologs: A2VDT9, Q08E62, Q20A00, Q2LZ58, Q5R8K0, Q6P4J6, Q7SYV9, Q7T346, Q8VD50, Q8VHZ5, Q8VHZ9, Q96D03, Q9D3F7, Q9NX09, Q9VTH4, Q9VTI8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	DDIT4	“transcriptional regulation”
DDIT4	“up-regulates activity”	TSC2	binding
TXNIP	“up-regulates quantity by stabilization”	DDIT4	binding
PRKN	“down-regulates quantity by destabilization”	DDIT4	ubiquitination
GSK3B	“down-regulates quantity by destabilization”	DDIT4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neddylation	6	15.8×	4e-04
Antigen processing: Ubiquitination & Proteasome degradation	5	10.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	5	11.9×	8e-03
protein ubiquitination	6	11.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

38 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

129 predictions. Top by Δscore:

Variant	Effect	Δscore
10:72274417:GGAAG:G	donor_gain	1.0000
10:72274418:G:GT	donor_gain	1.0000
10:72274419:A:T	donor_gain	1.0000
10:72274420:AGG:A	donor_loss	1.0000
10:72274421:GGTGA:G	donor_loss	1.0000
10:72274423:T:G	donor_loss	1.0000
10:72274680:T:TA	acceptor_gain	1.0000
10:72274690:TCCAG:T	acceptor_loss	1.0000
10:72274691:CCA:C	acceptor_loss	1.0000
10:72274692:CAG:C	acceptor_loss	1.0000
10:72274693:A:AG	acceptor_gain	1.0000
10:72274693:A:T	acceptor_loss	1.0000
10:72274694:G:A	acceptor_loss	1.0000
10:72274694:G:GA	acceptor_gain	1.0000
10:72274694:GA:G	acceptor_gain	1.0000
10:72274694:GAC:G	acceptor_gain	1.0000
10:72274694:GACA:G	acceptor_gain	1.0000
10:72274694:GACAC:G	acceptor_gain	1.0000
10:72274155:A:AG	acceptor_gain	0.9900
10:72274155:AGC:A	acceptor_gain	0.9900
10:72274156:G:GG	acceptor_gain	0.9900
10:72274156:GC:G	acceptor_gain	0.9900
10:72274156:GCG:G	acceptor_gain	0.9900
10:72274422:G:GG	donor_gain	0.9900
10:72274678:T:TA	acceptor_gain	0.9900
10:72274057:GCTG:G	donor_gain	0.9800
10:72274155:AGCG:A	acceptor_gain	0.9800
10:72274156:GCGG:G	acceptor_gain	0.9800
10:72274156:GCGGC:G	acceptor_gain	0.9800
10:72274418:GAAG:G	donor_gain	0.9800

AlphaMissense

1475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:72274881:T:C	L131P	1.000
10:72274902:A:T	E138V	1.000
10:72274905:C:A	P139Q	1.000
10:72274911:G:A	G141D	1.000
10:72274911:G:T	G141V	1.000
10:72274919:G:A	G144R	1.000
10:72274919:G:C	G144R	1.000
10:72274920:G:A	G144E	1.000
10:72275006:T:C	F173L	1.000
10:72275007:T:C	F173S	1.000
10:72275008:C:A	F173L	1.000
10:72275008:C:G	F173L	1.000
10:72275013:T:C	L175P	1.000
10:72275129:T:C	F214L	1.000
10:72275130:T:C	F214S	1.000
10:72275131:C:A	F214L	1.000
10:72275131:C:G	F214L	1.000
10:72275141:A:G	K218E	1.000
10:72275143:G:C	K218N	1.000
10:72275143:G:T	K218N	1.000
10:72274890:T:C	L134P	0.999
10:72274893:C:A	A135D	0.999
10:72274902:A:C	E138A	0.999
10:72274902:A:G	E138G	0.999
10:72274903:G:C	E138D	0.999
10:72274903:G:T	E138D	0.999
10:72274904:C:T	P139S	0.999
10:72274907:T:C	C140R	0.999
10:72274910:G:C	G141R	0.999
10:72274910:G:T	G141C	0.999

dbSNP variants (sampled 300 via entrez): RS1000527268 (10:72274634 C>A,G,T), RS1001078911 (10:72272357 G>A,C,T), RS1001612398 (10:72276108 A>C,T), RS1001877971 (10:72275040 G>A,C,T), RS1001945799 (10:72276370 A>G), RS1002557726 (10:72275362 C>G,T), RS1003155320 (10:72276456 T>C), RS1003622564 (10:72273704 G>A,T), RS1003922131 (10:72272688 G>A), RS1003955538 (10:72273908 G>T), RS1005333913 (10:72275588 A>AG,AGGG), RS1005556271 (10:72275380 G>A), RS1005984942 (10:72275594 G>A,C), RS1006014469 (10:72275459 A>G), RS1008016488 (10:72272976 C>T)

Disease associations

OMIM: gene MIM:607729 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002579_13	Heschl’s gyrus morphology	7.000000e-06
GCST006988_115	Blond vs. brown/black hair color	1.000000e-10
GCST008825_3	Body mass index	2.000000e-06
GCST010002_290	Refractive error	2.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

195 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Oxygen	affects reaction, decreases reaction, increases expression, affects binding, increases reaction (+1 more)	6
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	6
Cisplatin	decreases expression, increases expression	5
Estradiol	affects expression, decreases expression, increases expression	5
Cyclosporine	increases expression	5
Hydrogen Peroxide	affects expression, decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	4
Aflatoxin B1	affects expression, decreases expression	4
bisphenol A	increases expression	3
trichostatin A	affects cotreatment, increases expression	3
cobaltous chloride	decreases reaction, increases expression, affects reaction, increases reaction, decreases activity	3
Acetaminophen	increases expression, affects cotreatment	3
Cannabidiol	affects cotreatment, decreases expression, increases expression	3
Copper	increases expression, affects cotreatment, increases abundance, affects binding	3
Fluorouracil	increases expression	3
Dronabinol	affects cotreatment, increases expression, decreases expression	3
Tretinoin	decreases expression, increases expression	3
Tunicamycin	increases expression	3
methylmercuric chloride	decreases expression	2
sodium arsenite	decreases expression, increases expression	2
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	2
azaspiracid	increases expression	2
Ethanol	decreases expression, increases abundance, affects cotreatment, increases expression	2
Arsenic	increases expression, decreases ubiquitination, affects cotreatment, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Drugs, Chinese Herbal	increases expression	2
Lipopolysaccharides	increases expression, affects expression, affects response to substance, affects cotreatment	2
Metformin	affects cotreatment, increases expression, decreases expression	2
Phthalic Acids	affects cotreatment, increases expression, increases methylation	2
Progesterone	increases expression	2

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1W2	Abcam A-549 DDIT4 KO	Cancer cell line	Male
CVCL_D2AH	Abcam HCT 116 DDIT4 KO	Cancer cell line	Male
CVCL_D8JW	Ubigene HCT 116 DDIT4 KO	Cancer cell line	Male
CVCL_E0BJ	Ubigene HeLa DDIT4 KO	Cancer cell line	Female
CVCL_E1J7	HyCyte ARPE-19 KO-hDDIT4	Spontaneously immortalized cell line	Male
CVCL_SK57	HAP1 DDIT4 (-) 1	Cancer cell line	Male
CVCL_SK58	HAP1 DDIT4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.