RAET1G

Summary

RAET1G (retinoic acid early transcript 1G, HGNC:16795) is a protein-coding gene on chromosome 6q25.1, encoding UL-16 binding protein 5 (Q6H3X3). Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity.

This gene encodes a member of the major histocompatibility complex (MHC) class I family of proteins. Although the encoded protein includes C-terminal transmembrane and cytoplasmic domains, proteolytic processing results in the removal of these domains and subsequent tethering to the plasma membrane by a glycosylphosphatidylinositol (GPI)-anchor. The encoded protein is one of several related ligands of the natural killer group 2, member D (NKG2D) receptor, which functions as an activating receptor in innate and adaptive immunity. This gene is present in a gene cluster on chromosome 6.

Source: NCBI Gene 353091 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 25 total
• MANE Select transcript: NM_001001788

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16795
Approved symbol	RAET1G
Name	retinoic acid early transcript 1G
Location	6q25.1
Locus type	gene with protein product
Status	Approved
Aliases	ULBP5
Ensembl gene	ENSG00000203722
Ensembl biotype	protein_coding
OMIM	609244
Entrez	353091

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 nonsense_mediated_decay

ENST00000367360, ENST00000367361, ENST00000479265, ENST00000962108

RefSeq mRNA: 1 — MANE Select: NM_001001788 NM_001001788

CCDS: CCDS43514

Canonical transcript exons

ENST00000367360 — 5 exons

Exon	Start	End
ENSE00001444324	149916878	149917074
ENSE00001444325	149918174	149918384
ENSE00001890544	149922926	149923121
ENSE00002452156	149919043	149919324
ENSE00002496746	149919553	149919816

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 85.58.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7955 / max 116.5617, expressed in 512 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76156	1.7955	512

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus mucosa	UBERON:0002469	85.58	gold quality
lower esophagus mucosa	UBERON:0035834	84.77	gold quality
left adrenal gland	UBERON:0001234	83.02	gold quality
right adrenal gland	UBERON:0001233	82.87	gold quality
left adrenal gland cortex	UBERON:0035825	82.22	gold quality
right adrenal gland cortex	UBERON:0035827	80.89	gold quality
adrenal gland	UBERON:0002369	79.11	gold quality
vagina	UBERON:0000996	74.05	gold quality
stromal cell of endometrium	CL:0002255	72.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	72.09	gold quality
esophagus	UBERON:0001043	69.31	gold quality
omental fat pad	UBERON:0010414	67.61	gold quality
ectocervix	UBERON:0012249	66.23	gold quality
skin of abdomen	UBERON:0001416	65.68	gold quality
zone of skin	UBERON:0000014	65.06	gold quality
skin of leg	UBERON:0001511	64.70	gold quality
smooth muscle tissue	UBERON:0001135	63.22	gold quality
uterine cervix	UBERON:0000002	63.13	gold quality
metanephros cortex	UBERON:0010533	62.48	gold quality
calcaneal tendon	UBERON:0003701	62.13	gold quality
right coronary artery	UBERON:0001625	60.99	gold quality
endocervix	UBERON:0000458	60.87	gold quality
urinary bladder	UBERON:0001255	60.75	gold quality
minor salivary gland	UBERON:0001830	60.33	gold quality
adipose tissue	UBERON:0001013	60.19	gold quality
left uterine tube	UBERON:0001303	60.13	gold quality
saliva-secreting gland	UBERON:0001044	60.09	gold quality
ovary	UBERON:0000992	59.48	gold quality
right ovary	UBERON:0002118	59.47	gold quality
primary visual cortex	UBERON:0002436	59.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

Literature-anchored findings (GeneRIF, showing 5)

• Binds the activating receptor NKG2D and the the human cytomegalovirus protein UL16. (PMID:15240696)
• the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality. (PMID:19223974)
• RAET1G, like ULBP2, appears broadly expressed, but exhibits a lower apparent avidity for NKG2D due to a mutation in the center of the MHC-like fold. (PMID:19424970)
• RAET1G is regulated post-translationally to produce a GPI-anchored isoform (PMID:20304922)
• Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells. (PMID:25212604)

Cross-species orthologs

12 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	Ulbp1	ENSMUSG00000079685

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), RAET1E (ENSG00000164520), 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

UL-16 binding protein 5 — Q6H3X3 (reviewed: Q6H3X3)

Alternative names: Retinoic acid early transcript 1G protein

All UniProt accessions (2): Q6H3X3, C9JAK3

UniProt curated annotations — full annotation on UniProt →

Function. Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity. Down-regulates the expression of KLRK1 and stimulates natural killer cells to secrete IFNG. Stimulates natural killer cells to secrete IFNG.

Subunit / interactions. Interacts with KLRK1/NKG2D. (Microbial infection) In CMV-infected cells, interacts with the viral glycoprotein UL16; this interaction causes RAET1G retention in the endoplasmic reticulum and cis-Golgi and prevents binding to and activation of KLRK1/NKG2D, providing CMV with an immune evasion mechanism.

Subcellular location. Cell membrane. Endoplasmic reticulum Secreted.

Tissue specificity. Isoform 1 is highly expressed in colon and in a number of tumor cell lines and highly restricted in normal tissues. Both isoforms are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers.

Post-translational modifications. The functional form is cleaved C-terminally of the GPI-anchor and yields a 28 kDa protein.

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 (3)

UniProt ID	Names	Canonical?
Q6H3X3-1	1, RAET1G1	yes
Q6H3X3-2	2, RAET1G2
Q6H3X3-3	3, RAET1G3

RefSeq proteins (1): NP_001001788* (*=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 (17 total): splice variant 3, disulfide bond 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, sequence variant 1, mutagenesis site 1, propeptide 1, transmembrane region 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6H3X3-F1	70.96	0.46

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 (1): 218

Disulfide bonds (2): 50–66, 127–190

Glycosylation sites (1): 82

Mutagenesis-validated functional residues (1):

Position	Phenotype
217	reduced cell surface expression.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins

MSigDB gene sets: 77 (showing top): GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_VIA_MHC_CLASS_IB, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, 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), positive regulation of natural killer cell cytokine production (GO:0002729), immune response (GO:0006955), natural killer cell mediated cytotoxicity (GO:0042267), 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 (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
membrane	2
positive regulation of leukocyte mediated cytotoxicity	1
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
natural killer cell cytokine production	1
positive regulation of natural killer cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of natural killer cell cytokine production	1
immune system process	1
response to stimulus	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
biological_process	1
signaling receptor binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAET1G	KLRK1	P26718	995
RAET1G	MICB	P79525	720
RAET1G	HCST	Q9UBK5	513
RAET1G	KLRF1	Q9NZS2	491
RAET1G	MICA	P79506	446
RAET1G	NCR1	O76036	432
RAET1G	SLC2A1	P11166	423
RAET1G	CD226	Q15762	419
RAET1G	CD69	Q07108	412
RAET1G	PVR	P15151	398
RAET1G	KLRG1	Q96E93	396
RAET1G	FCGRT	P55899	385
RAET1G	CD28	P10747	378
RAET1G	KLRC1	P26715	373
RAET1G	LCP2	Q13094	369

IntAct

8 interactions, top by confidence:

A	B	Type	Score
RAET1G	KLRK1	psi-mi:“MI:0915”(physical association)	0.700
KLRK1	RAET1G	psi-mi:“MI:0915”(physical association)	0.700
RAET1G	UL16	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (1): RAET1G (Proximity Label-MS)

ESM2 similar proteins: A0A0G2K7V7, C1ITJ8, O08602, O08603, O08604, O19477, O35799, P01901, P01902, P06339, P13599, P14427, P14432, P16391, P25311, P26151, P30383, P55899, P60018, P70387, Q01965, Q29980, Q29983, Q2KN22, Q30201, Q3B8P2, Q5RD09, Q60I18, Q61559, Q63678, Q64726, Q6H3X3, Q8HWB0, Q8HWE5, Q8HWE7, Q8SPV9, Q8VD31, Q920A9, Q95460, Q9BCU3

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

997 predictions. Top by Δscore:

Variant	Effect	Δscore
6:149922924:A:T	donor_loss	1.0000
6:149922924:ACCGG:A	donor_gain	1.0000
6:149922925:CCGGC:C	donor_gain	1.0000
6:149922920:ACTC:A	donor_loss	0.9900
6:149922924:A:AC	donor_gain	0.9900
6:149922925:C:CC	donor_gain	0.9900
6:149922925:CCGG:C	donor_gain	0.9900
6:149919777:T:C	acceptor_gain	0.9800
6:149922919:AACT:A	donor_loss	0.9800
6:149919817:C:CC	acceptor_gain	0.9700
6:149922924:AC:A	donor_gain	0.9700
6:149922925:CC:C	donor_gain	0.9700
6:149922925:CCG:C	donor_gain	0.9700
6:149919813:GGGT:G	acceptor_gain	0.9600
6:149919814:GGT:G	acceptor_gain	0.9500
6:149919815:GTCTG:G	acceptor_loss	0.9500
6:149919817:CTGTG:C	acceptor_loss	0.9500
6:149919818:T:C	acceptor_loss	0.9500
6:149919610:C:CT	donor_gain	0.9400
6:149919551:AC:A	donor_gain	0.9300
6:149919552:CC:C	donor_gain	0.9300
6:149922238:TCAG:T	acceptor_gain	0.9300
6:149919812:AGGGT:A	acceptor_gain	0.9200
6:149917075:C:CC	acceptor_gain	0.9100
6:149919044:T:TA	donor_gain	0.9100
6:149917536:T:TC	acceptor_gain	0.9000
6:149918168:CCATA:C	donor_loss	0.9000
6:149918169:CATA:C	donor_loss	0.9000
6:149918170:ATAC:A	donor_loss	0.9000
6:149918171:TACCT:T	donor_loss	0.9000

AlphaMissense

2182 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:149919719:A:C	F61L	0.949
6:149919719:A:T	F61L	0.949
6:149919721:A:G	F61L	0.949
6:149919202:A:G	W158R	0.928
6:149919202:A:T	W158R	0.928
6:149919221:A:C	F151L	0.926
6:149919221:A:T	F151L	0.926
6:149919223:A:G	F151L	0.926
6:149919230:G:C	F148L	0.916
6:149919230:G:T	F148L	0.916
6:149919232:A:G	F148L	0.916
6:149919200:C:A	W158C	0.910
6:149919200:C:G	W158C	0.910
6:149919160:A:G	W172R	0.893
6:149919160:A:T	W172R	0.893
6:149919167:T:A	K169N	0.891
6:149919167:T:G	K169N	0.891
6:149919259:A:G	W139R	0.887
6:149919259:A:T	W139R	0.887
6:149919158:C:A	W172C	0.886
6:149919158:C:G	W172C	0.886
6:149919245:G:C	F143L	0.869
6:149919245:G:T	F143L	0.869
6:149919247:A:G	F143L	0.869
6:149919643:A:G	W87R	0.869
6:149919643:A:T	W87R	0.869
6:149919677:A:C	S75R	0.868
6:149919677:A:T	S75R	0.868
6:149919679:T:G	S75R	0.868
6:149919641:C:A	W87C	0.862

dbSNP variants (sampled 300 via entrez): RS1000219338 (6:149924088 C>T), RS1000277273 (6:149924353 T>G), RS1000287400 (6:149918792 G>A), RS1000405548 (6:149918917 C>A,G), RS1001072402 (6:149920119 G>A), RS1002313082 (6:149921173 G>A,T), RS1002477409 (6:149921453 A>G), RS1003085710 (6:149917234 G>C), RS1003714587 (6:149923075 C>A), RS1003720005 (6:149922404 C>A,T), RS1003864377 (6:149923706 G>A,C), RS1004090931 (6:149918585 G>A), RS1004314665 (6:149923603 A>G), RS1004478262 (6:149923792 AG>A), RS1005872658 (6:149921079 A>G)

Disease associations

OMIM: gene MIM:609244 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010702_29	Subcortical volume (MOSTest)	7.000000e-11
GCST010703_317	Brain morphology (MOSTest)	7.000000e-22
GCST012489_101	Heel bone mineral density x serum urate levels interaction	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression, affects expression	2
sodium arsenate	decreases expression, increases abundance	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Mustard Gas	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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