RAET1E

Summary

RAET1E (retinoic acid early transcript 1E, HGNC:16793) is a protein-coding gene on chromosome 6q25.1, encoding Retinoic acid early transcript 1E (Q8TD07). Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity.

This gene belong to the RAET1 family, which consists of major histocompatibility complex (MHC) class I-related genes located in a cluster on chromosome 6q24.2-q25.3. This and RAET1G protein differ from other RAET1 proteins in that they have type I membrane-spanning sequences at their C termini rather than glycosylphosphatidylinositol anchor sequences. This protein functions as a ligand for NKG2D receptor, which is expressed on the surface of several types of immune cells, and is involved in innate and adaptive immune responses. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 135250 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 39 total
• MANE Select transcript: NM_001394057

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16793
Approved symbol	RAET1E
Name	retinoic acid early transcript 1E
Location	6q25.1
Locus type	gene with protein product
Status	Approved
Aliases	LETAL, bA350J20.7, ULBP4
Ensembl gene	ENSG00000164520
Ensembl biotype	protein_coding
OMIM	609243
Entrez	135250

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000357183, ENST00000367363, ENST00000392270, ENST00000524905, ENST00000529948, ENST00000532335

RefSeq mRNA: 6 — MANE Select: NM_001394057 NM_001243325, NM_001243327, NM_001243328, NM_001394056, NM_001394057, NM_139165

CCDS: CCDS5221, CCDS59042, CCDS59043, CCDS59044

Canonical transcript exons

ENST00000357183 — 6 exons

Exon	Start	End
ENSE00001085087	149889885	149890145
ENSE00001920488	149890817	149891034
ENSE00002164439	149898021	149898113
ENSE00002187596	149883179	149888667
ENSE00002195117	149895846	149896032
ENSE00003548489	149889348	149889623

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 92.47.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4149 / max 33.0213, expressed in 131 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76151	0.1962	80
76155	0.1716	54
76153	0.0303	9
76154	0.0168	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus mucosa	UBERON:0002469	92.47	gold quality
lower esophagus mucosa	UBERON:0035834	92.18	gold quality
zone of skin	UBERON:0000014	81.01	gold quality
skin of abdomen	UBERON:0001416	80.99	gold quality
skin of leg	UBERON:0001511	80.85	gold quality
vagina	UBERON:0000996	79.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.13	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	75.82	gold quality
esophagus	UBERON:0001043	70.20	gold quality
calcaneal tendon	UBERON:0003701	66.03	gold quality
omental fat pad	UBERON:0010414	65.18	gold quality
tonsil	UBERON:0002372	63.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.34	gold quality
ectocervix	UBERON:0012249	60.54	gold quality
adult mammalian kidney	UBERON:0000082	60.17	gold quality
left adrenal gland	UBERON:0001234	59.67	gold quality
uterine cervix	UBERON:0000002	58.60	gold quality
urinary bladder	UBERON:0001255	58.59	gold quality
gastrocnemius	UBERON:0001388	58.47	gold quality
right coronary artery	UBERON:0001625	58.38	gold quality
left adrenal gland cortex	UBERON:0035825	58.20	gold quality
right adrenal gland	UBERON:0001233	58.14	gold quality
adrenal gland	UBERON:0002369	57.78	gold quality
sural nerve	UBERON:0015488	57.11	silver quality
muscle of leg	UBERON:0001383	56.88	gold quality
minor salivary gland	UBERON:0001830	56.74	gold quality
kidney	UBERON:0002113	56.63	gold quality
adipose tissue	UBERON:0001013	56.44	gold quality
spleen	UBERON:0002106	55.87	gold quality
saliva-secreting gland	UBERON:0001044	55.65	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.11
E-MTAB-7381	no	45.54
E-MTAB-2983	no	11.58
E-MTAB-6379	no	3.79

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 13)

• Binds the activating receptor NKG2D. (PMID:15240696)
• immune escape mechanism of tumors via alternative splicing of ULBP RNA to generate a free soluble ULBP protein, RAET1E2, that may impair NKG2D-mediated NK cell cytotoxicity to tumors (PMID:17470428)
• All ULBP4 splice variants (ULBP4-I, ULBP4-II and ULBP4-III) were type 1 membrane-spanning molecules and had the ability to bind with human NKG2D receptor in vitro (PMID:18544572)
• data suggest that ULBP4 functions as a ligand for both TCRgammadelta and NKG2D and may play a key role in immune surveillance of tumor development and clearance of viral infection (PMID:19436053)
• Patients whose tumors had high expression of RAET1E, ULBP1 and ULBP3 surviving a median of 11, 14 and 11 months, respectively, compared with disease-specific survival of 29, 30 and 25 months in patients whose tumors showed no expression of these ligands (PMID:20054857)
• genetic polymorphism among the ethnic groups (PMID:20219610)
• 5 of the 7 promoter polymorphisms of the RAET1E gene may disrupt transcription factor binding (PMID:26519211)
• RAET1E promoter polymorphism has increased to nine types, and there are now 12 alleles determined by the coding exons, including one null. (PMID:26814419)
• decreased expression levels of ULBP4 in NPC tissues as compared to that in normal NP epithelial tissues. In addition, low ULBP4 expression correlated with poor OS, DFS, DMFS, and may prove to be a novel prognostic factor. (PMID:28159927)
• Blocking the interaction of NKG2D with its ligands deleted the sensitizing effects of HCQ. In addition, we showed that HCQ did not affect the synthesis or degradation of ULBP4, but induced the translocation of ULBP4 from the cytoplasm to the cell membrane (PMID:28339029)
• An association of the raet1e polymorphisms with an increased risk of developing premature CAD and with cardiometabolic parameters has been shown for the first time. (PMID:30662365)
• Transcriptomic analysis of micropapillary high grade T1 urothelial bladder cancer. (PMID:33208770)
• The NKG2D ligand ULBP4 is not expressed by human monocytes. (PMID:33556116)

Cross-species orthologs

24 orthologs

Organism	Symbol	Gene ID
danio_rerio	mhc1laa	ENSDARG00000016056
danio_rerio	mhc1lba	ENSDARG00000016227
danio_rerio	mhc1lda	ENSDARG00000023203
danio_rerio		ENSDARG00000051710
danio_rerio		ENSDARG00000051711
danio_rerio	mhc1lfa	ENSDARG00000051712
danio_rerio	mhc1lga	ENSDARG00000051713
danio_rerio	mhc1lca	ENSDARG00000055813
danio_rerio	mhc1lja	ENSDARG00000096830
danio_rerio	si:dkey-52p2.5	ENSDARG00000096940
danio_rerio	mhc1lla	ENSDARG00000096977
mus_musculus	Raet1e	ENSMUSG00000053219
mus_musculus	Raet1d	ENSMUSG00000078452
rattus_norvegicus	AABR07000147.1	ENSRNOG00000023659
rattus_norvegicus	Raet1e	ENSRNOG00000040300
rattus_norvegicus	H60al	ENSRNOG00000042852
rattus_norvegicus	AABR07000137.1	ENSRNOG00000050129
rattus_norvegicus	LOC120098769	ENSRNOG00000062996
rattus_norvegicus	Raet1ll1	ENSRNOG00000063217
rattus_norvegicus	LOC120097698	ENSRNOG00000063801
rattus_norvegicus		ENSRNOG00000066542
rattus_norvegicus		ENSRNOG00000066949
rattus_norvegicus		ENSRNOG00000069337
rattus_norvegicus	H60bl1	ENSRNOG00000071074

Paralogs (22): HFE (ENSG00000010704), FCGRT (ENSG00000104870), ULBP1 (ENSG00000111981), ULBP2 (ENSG00000131015), ULBP3 (ENSG00000131019), MR1 (ENSG00000153029), RAET1L (ENSG00000155918), CD1D (ENSG00000158473), CD1A (ENSG00000158477), CD1C (ENSG00000158481), CD1B (ENSG00000158485), CD1E (ENSG00000158488), AZGP1 (ENSG00000160862), RAET1G (ENSG00000203722), MICB (ENSG00000204516), MICA (ENSG00000204520), HLA-C (ENSG00000204525), HLA-E (ENSG00000204592), HLA-G (ENSG00000204632), HLA-F (ENSG00000204642), HLA-A (ENSG00000206503), HLA-B (ENSG00000234745)

Protein

Protein identifiers

Retinoic acid early transcript 1E — Q8TD07 (reviewed: Q8TD07)

Alternative names: Lymphocyte effector toxicity activation ligand, NKG2D ligand 4, RAE-1-like transcript 4, UL16-binding protein 4

All UniProt accessions (2): Q8TD07, Q3T1D4

UniProt curated annotations — full annotation on UniProt →

Function. Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity.

Subunit / interactions. Binds to KLRK1/NKG2D. (Microbial infection) Contrary to other family members, does not interact with CMV glycoprotein UL16.

Subcellular location. Membrane Secreted.

Tissue specificity. Predominantly expressed in the skin, but also expressed in testis and trachea. Up-regulated in tumor cells of different origins. Expression progressively decreased after treatment of tumor cells with retinoic acid.

Domain organisation. MHC class I alpha-1 like and MHC class I alpha- like regions down-regulate the cell surface expression of KLRK1.

Miscellaneous. UL16-binding proteins (ULBPs) are unusual members of the extended MHC class I superfamily. They do not contain the alpha 3 domain and lack a transmembrane domain.

Similarity. Belongs to the MHC class I family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q8TD07-1	1, ULBP4, RAET1E	yes
Q8TD07-2	2, RL-4, ULBP4-II
Q8TD07-3	3
Q8TD07-4	4, RAET1E2
Q8TD07-5	5, ULBP4-III
Q8TD07-6	6, ULBP4-I

RefSeq proteins (6): NP_001230254, NP_001230256, NP_001230257, NP_001380985, NP_001380986, NP_631904 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011161	MHC_I-like_Ag-recog	Domain
IPR011162	MHC_I/II-like_Ag-recog	Homologous_superfamily
IPR037055	MHC_I-like_Ag-recog_sf	Homologous_superfamily
IPR050208	MHC_class-I_related	Family

Pfam: PF00129

UniProt features (25 total): sequence variant 7, splice variant 6, glycosylation site 3, topological domain 2, region of interest 2, signal peptide 1, chain 1, disulfide bond 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TD07-F1	81.87	0.53

Functional residue map

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

Disulfide bonds (1): 126–189

Glycosylation sites (3): 36, 154, 212

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

MSigDB gene sets: 92 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_VIA_MHC_CLASS_IB, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_POSITIVE_REGULATION_OF_T_CELL_MEDIATED_CYTOTOXICITY, chr6q25, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY

GO Biological Process (7): positive regulation of T cell mediated cytotoxicity (GO:0001916), antigen processing and presentation of endogenous peptide antigen via MHC class Ib (GO:0002476), antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent (GO:0002486), immune response (GO:0006955), natural killer cell mediated cytotoxicity (GO:0042267), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), immune system process (GO:0002376)

GO Molecular Function (2): natural killer cell lectin-like receptor binding (GO:0046703), protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of leukocyte mediated cytotoxicity	2
cellular anatomical structure	2
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
positive regulation of T cell mediated immunity	1
antigen processing and presentation of peptide antigen via MHC class Ib	1
antigen processing and presentation of endogenous peptide antigen	1
antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway	1
immune system process	1
response to stimulus	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
positive regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
biological_process	1
signaling receptor binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1

Protein interactions and networks

STRING

512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAET1E	KLRK1	P26718	998
RAET1E	HCST	Q9UBK5	714
RAET1E	CD8A	P01732	714
RAET1E	CD4	P01730	562
RAET1E	TYROBP	O43914	562
RAET1E	ULBP2	Q9BZM5	528
RAET1E	NECTIN2	Q92692	521
RAET1E	KLRF1	Q9NZS2	495
RAET1E	NCR1	O76036	484
RAET1E	CD1D	P15813	483
RAET1E	FCGR3A	P08637	479
RAET1E	CD226	Q15762	479
RAET1E	FCGR3B	O75015	467
RAET1E	NCR3	O14931	463
RAET1E	CD69	Q07108	457

IntAct

7 interactions, top by confidence:

A	B	Type	Score
RAET1E	KLRK1	psi-mi:“MI:0407”(direct interaction)	0.710
KLRK1	RAET1E	psi-mi:“MI:0915”(physical association)	0.710
RAET1E	GOLIM4	psi-mi:“MI:0914”(association)	0.350
RAET1E	IFNGR1	psi-mi:“MI:0914”(association)	0.350

BioGRID (37): NRN1 (Affinity Capture-MS), RYK (Affinity Capture-MS), ULBP2 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), SDK2 (Affinity Capture-MS), ULBP3 (Affinity Capture-MS), PODXL2 (Affinity Capture-MS), RAB3B (Affinity Capture-MS), FGFR2 (Affinity Capture-MS), IGDCC4 (Affinity Capture-MS), IFNGR1 (Affinity Capture-MS), MFAP3 (Affinity Capture-MS), GOLIM4 (Affinity Capture-MS), ALG11 (Affinity Capture-MS), ARL8B (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K7V7, C1ITJ8, O08602, O08603, O08604, O19477, O35799, O97945, P01572, P01573, P05001, P05011, P06799, P07349, P07350, P07351, P09235, P14431, P14432, P35849, P43626, P43627, P43628, P43632, P60018, P70387, P81255, Q29980, Q29983, Q30201, Q5VY80, Q60I18, Q61716, Q6H3X3, Q80SS5, Q80SU4, Q8HWB0, Q8HWE5, Q8HWE7, Q8N109

Diamond homologs: Q5VY80, Q6H3X3, Q8TD07, Q9BZM4, Q9BZM5, Q9BZM6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

429 predictions. Top by Δscore:

Variant	Effect	Δscore
6:149889884:CCA:C	donor_gain	1.0000
6:149889897:T:C	donor_gain	0.9900
6:149890042:C:CC	acceptor_gain	0.9900
6:149889623:TC:T	acceptor_loss	0.9800
6:149889624:C:T	acceptor_loss	0.9800
6:149889625:T:A	acceptor_loss	0.9800
6:149889879:ACTT:A	donor_loss	0.9800
6:149889880:CTTA:C	donor_loss	0.9800
6:149889882:TA:T	donor_loss	0.9800
6:149889883:A:AC	donor_gain	0.9800
6:149889883:A:C	donor_loss	0.9800
6:149889884:C:CC	donor_gain	0.9800
6:149889884:C:G	donor_loss	0.9800
6:149889423:T:TA	donor_gain	0.9700
6:149889476:CTGG:C	donor_gain	0.9700
6:149889624:C:CC	acceptor_gain	0.9700
6:149890815:A:AC	donor_gain	0.9700
6:149890816:C:CC	donor_gain	0.9700
6:149890816:CCAA:C	donor_gain	0.9700
6:149889471:T:TA	donor_gain	0.9600
6:149889475:A:AC	donor_gain	0.9600
6:149889476:C:CC	donor_gain	0.9600
6:149889882:TACC:T	donor_gain	0.9600
6:149889883:ACCA:A	donor_gain	0.9600
6:149889884:CCAC:C	donor_gain	0.9600
6:149890037:TTGTA:T	acceptor_gain	0.9600
6:149888668:C:CC	acceptor_gain	0.9500
6:149889878:CACTT:C	donor_loss	0.9500
6:149889883:AC:A	donor_gain	0.9500
6:149889884:CC:C	donor_gain	0.9500

AlphaMissense

1725 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:149889550:G:C	F140L	0.912
6:149889550:G:T	F140L	0.912
6:149889552:A:G	F140L	0.912
6:149889382:G:C	F196L	0.896
6:149889382:G:T	F196L	0.896
6:149889384:A:G	F196L	0.896
6:149889501:A:G	W157R	0.892
6:149889501:A:T	W157R	0.892
6:149890048:G:C	F61L	0.876
6:149890048:G:T	F61L	0.876
6:149890050:A:G	F61L	0.876
6:149889558:A:G	W138R	0.869
6:149889558:A:T	W138R	0.869
6:149890126:G:C	F35L	0.833
6:149890126:G:T	F35L	0.833
6:149890128:A:G	F35L	0.833
6:149889962:A:G	L90S	0.831
6:149889499:C:A	W157C	0.829
6:149889499:C:G	W157C	0.829
6:149889457:C:A	W171C	0.825
6:149889457:C:G	W171C	0.825
6:149889556:C:A	W138C	0.821
6:149889556:C:G	W138C	0.821
6:149889459:A:G	W171R	0.818
6:149889459:A:T	W171R	0.818
6:149890033:A:C	S66R	0.818
6:149890033:A:T	S66R	0.818
6:149890035:T:G	S66R	0.818
6:149890121:A:G	F37S	0.817
6:149889599:A:G	M124T	0.813

dbSNP variants (sampled 300 via entrez): RS1000129010 (6:149885163 T>G), RS1000248833 (6:149881983 A>G), RS1000301076 (6:149881579 C>G), RS1000381305 (6:149892932 A>C,G), RS1000465444 (6:149887659 C>A,T), RS1000547696 (6:149874092 T>A), RS1000549566 (6:149875493 A>G,T), RS1000583025 (6:149880560 A>C,G), RS1000635198 (6:149880088 T>A), RS1000729489 (6:149886592 G>A,T), RS1000784539 (6:149892343 A>G), RS1000825696 (6:149868549 A>C), RS1000856689 (6:149892040 C>A), RS1000939714 (6:149868741 C>T), RS1000982684 (6:149898959 G>A,T)

Disease associations

OMIM: gene MIM:609243 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010702_29	Subcortical volume (MOSTest)	7.000000e-11
GCST010703_317	Brain morphology (MOSTest)	7.000000e-22

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	increases expression, increases methylation	3
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
propionaldehyde	increases expression	1
arsenite	decreases methylation	1
avobenzone	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Copper	decreases expression, affects cotreatment	1
Estradiol	affects cotreatment, decreases expression	1
Formaldehyde	increases expression	1
Glucose	increases expression	1
Nicotine	increases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8NL	Abcam HCT 116 RAET1E KO	Cancer cell line	Male
CVCL_B9QX	Abcam A-549 RAET1E KO	Cancer cell line	Male
CVCL_D2H5	Abcam MCF-7 RAET1E KO	Cancer cell line	Female

Clinical trials (associated diseases)

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