TSC22D3

Summary

TSC22D3 (TSC22 domain family member 3, HGNC:3051) is a protein-coding gene on chromosome Xq22.3, encoding TSC22 domain family protein 3 (Q99576). Protects T-cells from IL2 deprivation-induced apoptosis through the inhibition of FOXO3A transcriptional activity that leads to the down-regulation of the pro-apoptotic factor BCL2L11.

This gene encodes the anti-inflammatory protein glucocorticoid (GC)-induced leucine zipper. Expression of this gene stimulated by glucocorticoids and interleukin 10 and it appears to play a key role in the anti-inflammatory and immunosuppressive effects of this steroid. This protein has also been shown to inhibit pro-inflammatory molecules including nuclear factor κB. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 1831 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 26 total
• Transcription factor: yes — 25 downstream targets (CollecTRI)
• MANE Select transcript: NM_198057

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3051
Approved symbol	TSC22D3
Name	TSC22 domain family member 3
Location	Xq22.3
Locus type	gene with protein product
Status	Approved
Aliases	DIP, GILZ, TSC-22R, hDIP
Ensembl gene	ENSG00000157514
Ensembl biotype	protein_coding
OMIM	300506
Entrez	1831

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 29 protein_coding

ENST00000315660, ENST00000372382, ENST00000372383, ENST00000372384, ENST00000372390, ENST00000372397, ENST00000480691, ENST00000486554, ENST00000502650, ENST00000502961, ENST00000503515, ENST00000505965, ENST00000506081, ENST00000506724, ENST00000510887, ENST00000514426, ENST00000514897, ENST00000688924, ENST00000892826, ENST00000892827, ENST00000892828, ENST00000892829, ENST00000892830, ENST00000892831, ENST00000936418, ENST00000950992, ENST00000950993, ENST00000950994, ENST00000950995

RefSeq mRNA: 5 — MANE Select: NM_198057 NM_001015881, NM_001318468, NM_001318470, NM_004089, NM_198057

CCDS: CCDS14530, CCDS14531, CCDS35365

Canonical transcript exons

ENST00000372383 — 3 exons

Exon	Start	End
ENSE00001457647	107775100	107775787
ENSE00001457703	107713221	107714749
ENSE00003656931	107715899	107715950

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 110.4883 / max 6331.8534, expressed in 1750 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200080	87.0060	1721
200077	9.2895	1101
200078	5.0519	923
200076	3.5019	1182
200079	2.0882	543
200083	1.5240	548
200084	0.9796	417
200082	0.4693	217
209774	0.3316	165
200085	0.1615	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.67	gold quality
mucosa of stomach	UBERON:0001199	99.62	gold quality
popliteal artery	UBERON:0002250	99.54	gold quality
tibial artery	UBERON:0007610	99.54	gold quality
tibial nerve	UBERON:0001323	99.51	gold quality
left coronary artery	UBERON:0001626	99.41	gold quality
aorta	UBERON:0000947	99.37	gold quality
blood	UBERON:0000178	99.34	gold quality
coronary artery	UBERON:0001621	99.31	gold quality
left uterine tube	UBERON:0001303	99.26	gold quality
calcaneal tendon	UBERON:0003701	99.26	gold quality
cardia of stomach	UBERON:0001162	99.25	gold quality
right ovary	UBERON:0002118	99.25	gold quality
olfactory bulb	UBERON:0002264	99.25	gold quality
ectocervix	UBERON:0012249	99.25	gold quality
ascending aorta	UBERON:0001496	99.18	gold quality
synovial joint	UBERON:0002217	99.18	gold quality
thoracic aorta	UBERON:0001515	99.17	gold quality
trachea	UBERON:0003126	99.17	gold quality
granulocyte	CL:0000094	99.16	gold quality
upper lobe of left lung	UBERON:0008952	99.15	gold quality
mononuclear cell	CL:0000842	99.14	gold quality
monocyte	CL:0000576	99.13	gold quality
leukocyte	CL:0000738	99.13	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.13	gold quality
pericardium	UBERON:0002407	99.12	gold quality
body of stomach	UBERON:0001161	99.10	gold quality
small intestine Peyer’s patch	UBERON:0003454	99.10	gold quality
descending thoracic aorta	UBERON:0002345	99.09	gold quality
decidua	UBERON:0002450	99.08	gold quality

Single-cell (SCXA)

Detected in 37 experiment(s), a significant marker in 27.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	9243.81
E-MTAB-4850	yes	4892.94
E-MTAB-6678	yes	4527.82
E-CURD-88	yes	3818.07
E-MTAB-8142	yes	3617.09
E-MTAB-9467	yes	3271.68
E-CURD-122	yes	3215.45
E-HCAD-1	yes	2781.33
E-MTAB-9221	yes	2413.97
E-MTAB-6379	yes	1891.83
E-GEOD-111727	yes	883.46
E-MTAB-8271	yes	403.88
E-HCAD-4	yes	168.69
E-MTAB-6701	yes	112.26
E-CURD-46	yes	74.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

25 targets.

Target	Regulation
BCL2L11
CCND1	Activation
CDKN1A	Repression
CFD
CSN2
CXCL10
DUSP1
FASLG
FKBP5
FOXO1	Repression
FOXO3	Repression
FOXO4	Repression
GSK3A
IFNGR2
IGFBP1
IL5
LPL
NFKB
PPARG	Repression
PTGS2	Unknown
RASL12
SGK1
TDRD1
TGFB1	Activation
TSC22D3

Upstream regulators (CollecTRI, top): CEBPA, CRTC2, ESR1, FOXO3, MYC, NR3C1, PAX1, POU2F1, TSC22D3, USF1

miRNA regulators (miRDB)

43 targeting TSC22D3, 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-3692-3P	99.98	70.27	2139
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-1301-3P	98.64	68.27	1071

Literature-anchored findings (GeneRIF, showing 40)

• Glucocorticoids and IL-10 stimulated macrophage production of GILZ, which displayed activities related to anti-inflammatory and immunosuppressive effects. (PMID:12393603)
• GILZ is a transiently expressed protein induced upon IL-2 withdrawal that protects T cells from the onset of apoptosis. (PMID:15031210)
• Overexpression of the Forkhead transcription factor FoxO3 enhances GC-induced gilz mRNA expression. (PMID:15705665)
• analysis of a novel link between GILZ and regulation of epithelial sodium transport through modulation of ERK signaling (PMID:16216878)
• GILZ is critical for commitment of DCs to differentiate into regulatory DCs and to the generation of antigen-specific Tregs. (PMID:17356131)
• multiple GILZ isoforms are expressed in most cells and tissues and that these play distinct roles in regulating proliferation and ion transport. (PMID:17956870)
• Lower basal plasma cortisol levels and a lower expression of corticosteroid receptors and GILZ in fibromyalgia patients when compared to healthy controls. (PMID:18468809)
• GILZ is a mediator of glucocorticoid killing, and is regulated by PI3-kinase/AKT. (PMID:18499442)
• Down-regulated expression of GILZ may contribute to the pathogenesis of CRSsNP and CRSwNP and associate with response to surgery. GILZ expression in the upper airways can be regulated differentially by different cytokines. (PMID:19260870)
• GILZ1 and SGK1 provide a physical and functional link between the PI3K- and Raf-1-dependent signaling modules (PMID:19380724)
• GILZ activates AKT, a crucial signaling molecule in tumorigenesis appearing as a potential key molecule in epithelial ovarian cancer. (PMID:19814803)
• Implication of the transcription factor GILZ in the pathophysiology of glucocorticoid-induced osteoporosis by regulating osteoblast maturation and bone turnover. (PMID:19875485)
• GILZ expression provokes a Crm-1-dependent nuclear exclusion of FOXO3 leading to its relocalization to the cytoplasm. (PMID:20018851)
• GILZ1 inhibits SGK1 ubiquitinylation and subsequent proteasome-mediated degradation, thereby prolonging its half-life and increasing its steady-state expression. (PMID:20947508)
• Taking into account the unique role of DCs within the allo-HSCT context, novel preventive and curative therapeutics for GVHD might be based on the selective induction of GILZ expression in vivo (PMID:20970683)
• UL14 of herpes simplex virus type 1 interacts with cellular factor TSC22D3 during replication. (PMID:21512757)
• The glucocorticoid-induced leucine zipper protein GILZ is a glucocorticoid-responsive molecule with signal transduction interactions, many of which are operative in inflammatory diseases; it could be a key endogenous regulator of the immune response. (PMID:21556028)
• Data show that together with GILZ, chemokine CX3CL1 emerges as a regulator of cell proliferation, which may be of potential clinical relevance for the selection of the most appropriate treatment for EOC patients. (PMID:21750716)
• these results demonstrate that GILZ is a key inhibitor of the mTORC2 pathway. (PMID:21804606)
• High GILZ mRNA expression was independently associated with increased risk for a high level of posttraumatic stress disorder symptoms. (PMID:22137507)
• The data showed a MyD88- and TTP-dependent GILZ downregulation in human macrophages upon Toll-like receptor activation. Suppression of GILZ is mediated by mRNA destabilization, which might represent a regulatory mechanism in macrophage activation. (PMID:22539300)
• Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. (PMID:22832853)
• DC-SCRIPT serves an important role in regulating GR function in DCs, corepressing GR-dependent upregulation of the tolerance-inducing transcription factor GILZ. (PMID:23440419)
• study suggests that GILZ variants are not common causes of SCO and NOA in Australian or American men (PMID:23494955)
• Inhibition of epithelial injury repair by dexamethasone is mediated in part by activation of GILZ. (PMID:23573276)
• Delta-sleep inducing peptide entrapment and release from polymer hydrogels based on modified polyvinyl alcohol in vitro (PMID:23650723)
• Exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-kappaB p65 DNA binding and MAPK activity. (PMID:23729444)
• PUVA directly stimulates GILZ expression. (PMID:24215840)
• Data show a diminished expression of the anti-inflammatory mediator GILZ in the inflamed vasculature and indicate that GILZ downregulation requires the mRNA binding protein ZFP36. (PMID:24747114)
• The N-terminal part of L-GILZ protein is responsible for Ras/L-GILZ protein-to-protein interaction, important for the control of proliferation rate of spermatogonia. (PMID:24993177)
• L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. (PMID:25168242)
• our data suggest that GILZ is a key regulator of macrophage functions. (PMID:25964494)
• results reveal GILZ to be a new actor in apoptosis regulation in neutrophil-like cells involving JNK and Mcl-1. (PMID:26384220)
• GILZ is a non-redundant regulator of B cell activity, with important potential clinical implications in systemic lupus erythematosus. (PMID:26612340)
• Overall, these results suggest that GILZ antagonizes the pro-inflammatory effects of TNFa in human adipocytes, and its downregulation in obesity may contribute to adipose inflammation and dysregulated adipokine production, and thereby systemic metabolism. (PMID:27178044)
• Under endoplasmic reticulum stress conditions, overexpression of GILZ significantly reduced activation of mitochondrial pathway of apoptosis by maintaining Bcl-xl level. GILZ protein affects the unfolded protein response signaling shifting the balance towards pro-survival signals as judged by down-regulation of CHOP, ATF4, XBP1s mRNA and increase in GRP78 protein level. (PMID:27416758)
• We propose a novel role of GILZ in contributing to corticoid-induced leptin and leptin receptor expression in osteoarthritis synovial fibroblasts (PMID:27716396)
• The mRNA expression of GILZ was significantly correlated with Systemic Lupus Erythematosus Disease Activity Index score. (PMID:28601944)
• TSC22D3 gene expression is significantly associated with long-term changes in Blood Pressure, providing a link between gene expression and Blood Pressure. (PMID:28784648)
• L-GILZ regulates thyroid cancer cell proliferation. (PMID:29467389)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:64189	ENSDARG00000033501
mus_musculus	Tsc22d3	ENSMUSG00000031431
rattus_norvegicus	Tsc22d3	ENSRNOG00000056135
drosophila_melanogaster	bun	FBGN0259176
caenorhabditis_elegans		WBGENE00011824
caenorhabditis_elegans		WBGENE00012994

Paralogs (3): TSC22D1 (ENSG00000102804), TSC22D4 (ENSG00000166925), TSC22D2 (ENSG00000196428)

Protein

Protein identifiers

TSC22 domain family protein 3 — Q99576 (reviewed: Q99576)

Alternative names: DSIP-immunoreactive peptide, Delta sleep-inducing peptide immunoreactor, Glucocorticoid-induced leucine zipper protein, TSC-22-like protein, TSC-22-related protein

All UniProt accessions (13): Q99576, A0A8I5KT94, D6R8Z7, D6R9J1, D6RAX8, D6RBL1, D6RCK9, D6RD37, D6RD92, D6RDZ7, D6RDZ9, E7EWD5, Q5JRJ0

UniProt curated annotations — full annotation on UniProt →

Function. Protects T-cells from IL2 deprivation-induced apoptosis through the inhibition of FOXO3A transcriptional activity that leads to the down-regulation of the pro-apoptotic factor BCL2L11. In macrophages, plays a role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL10. In T-cells, inhibits anti-CD3-induced NFKB1 nuclear translocation and thereby NFKB1 DNA-binding activities. In vitro, suppresses AP-1 transcription factor complex DNA-binding activities. Inhibits myogenic differentiation and mediates anti-myogenic effects of glucocorticoids by binding and regulating MYOD1 and HDAC1 transcriptional activity resulting in reduced expression of MYOG.

Subunit / interactions. Can form homodimers, however it is likely to function as a monomer. Interacts with NFKB1. Interacts (via N-terminus) with JUN and FOS; these interactions inhibit the binding of active AP1 to its target DNA. Interacts with MYOD1. Interacts with HDAC1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitously expressed, including in the fetal brain and liver. Expressed in brain, lung, spleen and skeletal muscle. Lower levels detected in heart and kidney. Not detected in the pancreas. In non-lymphoid tissues, in the absence of inflammation, the major source of constitutive expression is the macrophage lineage. Also expressed in cells from different hemopoietic cell lineages, including bone marrow cells, CD34+ stem cells, mature B- and T-cells, monocytes and granulocytes. Down-regulated in activated macrophages from inflammatory lesions of delayed-type hypersensitivity (DTH) reactions, such as in tuberculosis and in Crohn disease, whereas in Burkitt lymphoma, persists in macrophages involved in the phagocytosis of apoptotic malignant cells.

Domain organisation. The leucine-zipper is involved in homodimerization.

Induction. Induced in T-lymphocytes by IL2 deprivation.

Similarity. Belongs to the TSC-22/Dip/Bun family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99576-1	1	yes
Q99576-3	2
Q99576-5	3

RefSeq proteins (5): NP_001015881, NP_001305397, NP_001305399, NP_004080, NP_932174* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000580	TSC22/Bun	Family
IPR047862	TSC22/BUN_CS	Conserved_site

Pfam: PF01166

UniProt features (12 total): modified residue 5, region of interest 3, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99576-F1	72.61	0.17

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 (5): 73, 1, 1, 102, 42

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 479 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, KOBAYASHI_EGFR_SIGNALING_24HR_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, DORN_ADENOVIRUS_INFECTION_12HR_UP, PEREZ_TP63_TARGETS, GCANCTGNY_MYOD_Q6, MODULE_45, GOBP_T_CELL_HOMEOSTASIS, GOZGIT_ESR1_TARGETS_DN, AAGCCAT_MIR135A_MIR135B, GOBP_LYMPHOCYTE_HOMEOSTASIS

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), response to osmotic stress (GO:0006970), negative regulation of activation-induced cell death of T cells (GO:0070236)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
response to stress	1
response to abiotic stimulus	1
negative regulation of immune system process	1
activation-induced cell death of T cells	1
negative regulation of T cell apoptotic process	1
regulation of activation-induced cell death of T cells	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1049 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSC22D3	SGK1	O00141	866
TSC22D3	NR3C1	P04150	786
TSC22D3	FKBP5	Q13451	724
TSC22D3	TTLL5	Q6EMB2	713
TSC22D3	TTLL10	Q6ZVT0	713
TSC22D3	RAF1	P04049	702
TSC22D3	DUSP1	P28562	666
TSC22D3	DUSP12	Q9UNI6	582
TSC22D3	NCOA2	Q15596	562
TSC22D3	FOS	P01100	560
TSC22D3	LHX4	Q969G2	547
TSC22D3	NEDD4L	Q96PU5	546
TSC22D3	NFKB1	P19838	527
TSC22D3	FOXO3	O43524	520
TSC22D3	NR3C2	P08235	507

IntAct

44 interactions, top by confidence:

A	B	Type	Score
NRBP1	TSC22D2	psi-mi:“MI:0914”(association)	0.730
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
TSC22D4	TSC22D2	psi-mi:“MI:0914”(association)	0.640
TSC22D3	MAD1L1	psi-mi:“MI:0915”(physical association)	0.560
REL	TSC22D3	psi-mi:“MI:0915”(physical association)	0.560
FAM117B	GAPDHS	psi-mi:“MI:0914”(association)	0.530
MTA2	TSC22D3	psi-mi:“MI:0915”(physical association)	0.370
TSC22D3	DCLK2	psi-mi:“MI:0915”(physical association)	0.370
TSC22D3	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.370
TSC22D3	HPCAL4	psi-mi:“MI:0915”(physical association)	0.370
HSPA8	PPP6C	psi-mi:“MI:0914”(association)	0.350
NRBP2	HAX1	psi-mi:“MI:0914”(association)	0.350
PABPC4	HNRNPR	psi-mi:“MI:0914”(association)	0.350
RNF40	HNRNPR	psi-mi:“MI:0914”(association)	0.350
SLC7A6	DDX46	psi-mi:“MI:0914”(association)	0.350
FBXO10	BLTP3B	psi-mi:“MI:0914”(association)	0.350
CDC42SE2	SSC5D	psi-mi:“MI:0914”(association)	0.350
SPANXN2	ZNF320	psi-mi:“MI:0914”(association)	0.350
IQCN	TARS3	psi-mi:“MI:0914”(association)	0.350
SYNJ2BP	TARS3	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
CCT8L2	DVL2	psi-mi:“MI:0914”(association)	0.350
ZHX1-C8orf76	FANCG	psi-mi:“MI:0914”(association)	0.350
EID3	ACSL4	psi-mi:“MI:0914”(association)	0.350
TSC22D3	TSC22D2	psi-mi:“MI:0914”(association)	0.350
ADAM19	TSC22D2	psi-mi:“MI:0914”(association)	0.350
C1QL3	TSC22D2	psi-mi:“MI:0914”(association)	0.350
BDH2	CKS2	psi-mi:“MI:0914”(association)	0.350
TSC22D3	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350

BioGRID (103): TP53 (Reconstituted Complex), TSC22D3 (Affinity Capture-Western), TP53 (Affinity Capture-Western), MDM2 (Affinity Capture-Western), MAD1L1 (Two-hybrid), C19orf57 (Two-hybrid), TSC22D3 (Affinity Capture-MS), TSC22D3 (Affinity Capture-MS), TSC22D3 (Affinity Capture-MS), TSC22D3 (Affinity Capture-MS), PLEKHF2 (Two-hybrid), HPCAL4 (Two-hybrid), TP53 (Co-localization), MDM2 (Co-localization), TSC22D3 (Co-localization)

ESM2 similar proteins: A4IGP0, A4VY70, A4W4G5, A8H9H9, B0TPR8, I7GVL4, O76616, P05820, P08364, P0A382, P0CA97, P11077, P11078, P12397, P15480, P22047, P22351, P25219, P29802, P35259, P51737, P61825, P94594, Q04470, Q04916, Q06906, Q06VD5, Q09380, Q0PI70, Q16RI1, Q29E01, Q51887, Q53FT3, Q55385, Q568T4, Q56JY0, Q5M808, Q5RED5, Q5ZK09, Q6C3T0

Diamond homologs: E9Q7M2, O75157, P62500, P62501, P80220, Q22544, Q24522, Q24523, Q27I66, Q3B8N7, Q3MHL6, Q5R4H1, Q5RED5, Q99576, Q9EQN3, Q9EQZ1, Q9Y3Q8, Q9Z2S7, Q15714, Q4R4H5, Q91012

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
TSC22D3	“down-regulates activity”	RELA	binding
TSC22D3	“down-regulates activity”	NFKB2	binding
TSC22D3	“down-regulates activity”	NfKb-p65/p50	binding
CRTC2	“up-regulates quantity”	TSC22D3	“transcriptional regulation”
TSC22D3	“down-regulates activity”	FOXO1	relocalization
TSC22D3	“down-regulates activity”	FOXO3	relocalization
TSC22D3	“down-regulates activity”	FOXO4	relocalization
TSC22D3	“down-regulates activity”	FOXO	relocalization
NR3C1	“up-regulates quantity by expression”	TSC22D3	“transcriptional regulation”
TSC22D3	“down-regulates quantity by repression”	PPARG	“transcriptional regulation”
FOXO3	“up-regulates quantity by expression”	TSC22D3	“transcriptional regulation”
FOXO3	“up-regulates activity”	TSC22D3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

377 predictions. Top by Δscore:

Variant	Effect	Δscore
X:107714745:AGATC:A	acceptor_gain	1.0000
X:107714746:GATC:G	acceptor_gain	1.0000
X:107714748:TC:T	acceptor_gain	1.0000
X:107714749:CC:C	acceptor_gain	1.0000
X:107714753:CCAA:C	acceptor_gain	1.0000
X:107714754:C:CT	acceptor_gain	1.0000
X:107714754:C:T	acceptor_gain	1.0000
X:107714755:A:T	acceptor_gain	1.0000
X:107714756:A:AC	acceptor_gain	1.0000
X:107714756:A:C	acceptor_gain	1.0000
X:107715894:CTCA:C	donor_loss	1.0000
X:107715897:A:AC	donor_gain	1.0000
X:107715897:ACC:A	donor_loss	1.0000
X:107715898:C:A	donor_loss	1.0000
X:107715898:C:CC	donor_gain	1.0000
X:107715951:C:CC	acceptor_gain	1.0000
X:107713475:T:TC	acceptor_gain	0.9900
X:107714747:ATC:A	acceptor_gain	0.9900
X:107714750:C:CA	acceptor_loss	0.9900
X:107714750:C:CC	acceptor_gain	0.9900
X:107714751:T:G	acceptor_loss	0.9900
X:107715897:AC:A	donor_gain	0.9900
X:107715898:CC:C	donor_gain	0.9900
X:107715948:GCA:G	acceptor_gain	0.9900
X:107715949:CA:C	acceptor_gain	0.9900
X:107715949:CAC:C	acceptor_gain	0.9900
X:107715950:ACT:A	acceptor_loss	0.9900
X:107715951:C:CG	acceptor_loss	0.9900
X:107715955:C:CT	acceptor_gain	0.9900
X:107715956:A:T	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000072918 (X:107754518 A>G), RS1000090245 (X:107713646 T>G), RS1000238961 (X:107716163 TGCC>T,TGCCGCC), RS1000270041 (X:107715673 A>G), RS1000298518 (X:107726843 C>A), RS1000318293 (X:107722698 C>A,G), RS1000344963 (X:107754927 G>A), RS1000355690 (X:107730989 C>T), RS1000382708 (X:107765355 C>T), RS1000398341 (X:107740415 C>T), RS1000417742 (X:107731406 A>T), RS1000427257 (X:107777176 C>A), RS1000457746 (X:107736481 C>T), RS1000521385 (X:107749105 C>T), RS1000583852 (X:107722395 G>A)

Disease associations

OMIM: gene MIM:300506 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Dexamethasone	affects reaction, increases activity, affects cotreatment, decreases reaction, increases reaction (+5 more)	11
Estradiol	affects cotreatment, increases reaction, decreases expression, decreases reaction, increases expression (+1 more)	7
Formaldehyde	increases expression	5
Cisplatin	affects expression, increases expression	4
Progesterone	affects cotreatment, increases expression	4
Tretinoin	affects cotreatment, decreases expression, increases expression	4
Particulate Matter	affects cotreatment, increases abundance, increases expression, affects expression, increases reaction (+1 more)	4
sodium arsenite	decreases expression, increases expression	3
Acetaminophen	affects expression, increases expression	3
bisphenol A	increases expression, decreases expression	2
bisphenol S	affects reaction, increases expression, decreases expression	2
Arsenic Trioxide	affects cotreatment, decreases expression, affects binding, decreases reaction, increases expression (+1 more)	2
Fulvestrant	decreases reaction, increases expression, increases reaction	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Vehicle Emissions	affects expression, increases reaction, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Calcitriol	decreases expression	2
Dichlorodiphenyl Dichloroethylene	decreases expression, increases activity	2
Smoke	decreases expression, increases abundance, increases expression	2
Dronabinol	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tunicamycin	increases expression	2
Mifepristone	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Cyclosporine	increases expression	2
GSK-J4	increases expression	1
afuresertib	increases expression	1
bisphenol F	decreases expression	1
mivebresib	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1

Clinical trials (associated diseases)

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