MR1

Summary

MR1 (major histocompatibility complex, class I-related, HGNC:4975) is a protein-coding gene on chromosome 1q25.3, encoding Major histocompatibility complex class I-related protein 1 (Q95460). Antigen-presenting molecule specialized in displaying microbial pyrimidine-based metabolites to alpha-beta T cell receptors (TCR) on innate-type mucosal-associated invariant T (MAIT) cells.

MAIT (mucosal-associated invariant T-cells) lymphocytes represent a small population of T-cells primarily found in the gut. The protein encoded by this gene is an antigen-presenting molecule that presents metabolites of microbial vitamin B to MAITs. This presentation may activate the MAITs to regulate the amounts of specific types of bacteria in the gut. Several transcript variants encoding different isoforms have been found for this gene, and a pseudogene of it has been detected about 36 kbp upstream on the same chromosome.

Source: NCBI Gene 3140 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 73 total
• Druggable target: yes
• MANE Select transcript: NM_001385161

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4975
Approved symbol	MR1
Name	major histocompatibility complex, class I-related
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000153029
Ensembl biotype	protein_coding
OMIM	600764
Entrez	3140

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000282990, ENST00000367578, ENST00000367579, ENST00000367580, ENST00000434571, ENST00000438435, ENST00000486453, ENST00000614012, ENST00000617803, ENST00000683652, ENST00000684375, ENST00000684662, ENST00000969608

RefSeq mRNA: 9 — MANE Select: NM_001385161 NM_001194999, NM_001195000, NM_001195035, NM_001310213, NM_001385161, NM_001385162, NM_001385163, NM_001385164, NM_001531

CCDS: CCDS1342, CCDS53440, CCDS53441, CCDS53442, CCDS91120

Canonical transcript exons

ENST00000367580 — 6 exons

Exon	Start	End
ENSE00001068608	181052235	181052510
ENSE00002365388	181055225	181061938
ENSE00003493176	181050011	181050286
ENSE00003501391	181053573	181053677
ENSE00003561688	181049052	181049312
ENSE00003911082	181033983	181034074

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 96.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.7141 / max 79.6840, expressed in 1409 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6980	5.7141	1409

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	96.41	gold quality
olfactory bulb	UBERON:0002264	93.40	gold quality
palpebral conjunctiva	UBERON:0001812	90.90	gold quality
monocyte	CL:0000576	89.86	gold quality
mononuclear cell	CL:0000842	89.39	gold quality
leukocyte	CL:0000738	89.31	gold quality
diaphragm	UBERON:0001103	89.08	silver quality
vena cava	UBERON:0004087	88.25	gold quality
stromal cell of endometrium	CL:0002255	87.33	gold quality
blood	UBERON:0000178	87.24	gold quality
visceral pleura	UBERON:0002401	87.22	gold quality
calcaneal tendon	UBERON:0003701	86.64	gold quality
smooth muscle tissue	UBERON:0001135	86.44	gold quality
granulocyte	CL:0000094	85.71	gold quality
pleura	UBERON:0000977	84.97	gold quality
gall bladder	UBERON:0002110	84.87	gold quality
parietal pleura	UBERON:0002400	84.64	gold quality
thymus	UBERON:0002370	84.34	silver quality
epithelium of nasopharynx	UBERON:0001951	84.33	gold quality
nasopharynx	UBERON:0001728	84.32	gold quality
bone marrow	UBERON:0002371	84.32	gold quality
bone marrow cell	CL:0002092	84.29	gold quality
lymph node	UBERON:0000029	84.05	gold quality
nasal cavity epithelium	UBERON:0005384	83.97	silver quality
islet of Langerhans	UBERON:0000006	83.86	gold quality
descending thoracic aorta	UBERON:0002345	83.86	gold quality
thoracic aorta	UBERON:0001515	83.62	gold quality
ascending aorta	UBERON:0001496	83.54	gold quality
right coronary artery	UBERON:0001625	83.49	gold quality
bone element	UBERON:0001474	83.40	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.72
E-MTAB-7303	no	7.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, NFKB

miRNA regulators (miRDB)

191 targeting MR1, 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-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 40)

• MR1 molecules can associate with the peptide-loading complex and can be detected at low levels at the surface of transfected cells. (PMID:12794138)
• Our results demonstrated a preferential association of MR1 with beta(2)-microglobulin in MHC class I-deficient B cell lines. (PMID:18068122)
• the presentation pathway of MR1 to MAIT cells is highly evolutionarily conserved (PMID:19416870)
• Induction of MHC class I-like antigen is associated with relapsed chronic myeloid leukemia. (PMID:19706888)
• a function for MR1 in the development of IgA producing plasma cells. (PMID:19760593)
• fact that MR1 seems mainly intracellular might offer clues as to the process, given the precedence in other class I molecules (PMID:21190736)
• Taken together these results strongly suggest that MR1 needs to bind proteasome-independent ligands in order to properly reach the cell surface. (PMID:21777569)
• Mutagenesis of MR1 showed that only two residues, which were centrally positioned and on opposing sides of the antigen-binding cleft of MR1, were essential for MAIT cell activation (PMID:22412157)
• Human thymic MR1-restricted MAIT cells are innate pathogen-reactive effectors that adapt following thymic egress. (PMID:22692454)
• metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance; as many vitamin biosynthetic pathways are unique to bacteria and yeast, data suggest that MAIT cells use these metabolites to detect microbial infection (PMID:23051753)
• A novel MR1B isoform probably plays a physiological role complementary to MR1A with respect to mucosal-associated invariant T cells development and/or function. (PMID:23457030)
• MR1 tetramers allow precise phenotypic characterization of human and mouse mucosal-associated invariant T cells. (PMID:24101382)
• [review] Mucosal-associated invariant T-cell (MAIT) T-cell antigen receptor recognizes riboflavin and folic acid metabolites bound by MR1 in a conserved docking mode and thus acts like a pattern recognition receptor. (PMID:24556396)
• Mucosal-associated invariant T cell adaptation was a direct consequence of exposure to various exogenous MR1-restricted epitopes. (PMID:25049333)
• Data indicate that high expression of CD26 ia a specific markers to define major histocompatibility complex, class I-like sequence protein MR1-restricted mucosa-associated invariant T (MAIT) cells. (PMID:25752900)
• Studies indicate that the antigen-presenting molecules CD1 and MHC class I-related protein (MR1) display lipids and small molecules to T cells. (PMID:26388332)
• results suggest that high expression of MR-1 is involved in hepatocellular carcinoma progression (PMID:26823810)
• endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment (PMID:27031111)
• Data show that the major histocompatibility complex, class I-related protein (MR1) antigen presentation is characterized by a rapid ‘off-on-off’ mechanism that is strictly dependent on antigen availability. (PMID:27043408)
• we have shown that MR1-mediated MAIT cell activation is tightly regulated at several levels. Efficient MR1-mediated MAIT cell activation requires both intact bacteria to access an acidified endolysomal compartment and activation of the APC through NF-kappaB or interferon signaling pathways. (PMID:27105778)
• Polymorphism in MR1 gene is associated with susceptibility to tuberculosis. (PMID:27881839)
• Early endosomal TLR9 activation is important for MR1-mediated bacterial antigen presentation in B cells. (PMID:28518215)
• Human mucosal-associated invariant T cells possess capacity for B cell help via MR1-mediated immunoglobulins production. (PMID:28807929)
• Role of CD1d- and MR1-Restricted T Cells in Asthma. (PMID:30210497)
• MR1 recycling and blockade of endosomal trafficking reveal distinguishable antigen presentation pathways between Mycobacterium tuberculosis infection and exogenously delivered antigens. (PMID:30886396)
• The BCG-induced IFN-gamma expression by MAIT cells in vitro was mediated by the innate cytokines IL-12 and IL-18 more than MR1-induced TCR signaling, suggesting TCR-independent activation. (PMID:31611259)
• BCL11B regulates MICA/B-mediated immune response by acting as a competitive endogenous RNA. (PMID:31673069)
• MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1. (PMID:31826876)
• this study reports MR1 as a ligand for human gamma delta T cells and redefines the parameters for TCR recognition. (PMID:31857486)
• Virus-Mediated Suppression of the Antigen Presentation Molecule MR1. (PMID:32130899)
• Opsonization-Enhanced Antigen Presentation by MR1 Activates Rapid Polyfunctional MAIT Cell Responses Acting as an Effector Arm of Humoral Antibacterial Immunity. (PMID:32434941)
• Atypical TRAV1-2(-) T cell receptor recognition of the antigen-presenting molecule MR1. (PMID:32817339)
• Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens. (PMID:32958637)
• Alternative splicing of MR1 regulates antigen presentation to MAIT cells. (PMID:32963314)
• Rab6 regulates recycling and retrograde trafficking of MR1 molecules. (PMID:33247182)
• Antigen specificities and functional properties of MR1-restricted T cells. (PMID:33358568)
• T cell receptor diversity, specificity and promiscuity of functionally heterogeneous human MR1-restricted T cells. (PMID:33360378)
• MR1 encompasses at least six allele groups with coding region alterations. (PMID:34351076)
• Recognition of the antigen-presenting molecule MR1 by a Vdelta3(+) gammadelta T cell receptor. (PMID:34845016)
• The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation. (PMID:34968463)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mr1	ENSMUSG00000026471
rattus_norvegicus	Mr1	ENSRNOG00000003522

Paralogs (22): HFE (ENSG00000010704), FCGRT (ENSG00000104870), ULBP1 (ENSG00000111981), ULBP2 (ENSG00000131015), ULBP3 (ENSG00000131019), RAET1L (ENSG00000155918), CD1D (ENSG00000158473), CD1A (ENSG00000158477), CD1C (ENSG00000158481), CD1B (ENSG00000158485), CD1E (ENSG00000158488), AZGP1 (ENSG00000160862), RAET1E (ENSG00000164520), 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

Major histocompatibility complex class I-related protein 1 — Q95460 (reviewed: Q95460)

Alternative names: Class I histocompatibility antigen-like protein

All UniProt accessions (4): Q95460, A0A804HIG0, A0A804HJC9, A0A8C8PVM5

UniProt curated annotations — full annotation on UniProt →

Function. Antigen-presenting molecule specialized in displaying microbial pyrimidine-based metabolites to alpha-beta T cell receptors (TCR) on innate-type mucosal-associated invariant T (MAIT) cells. In complex with B2M preferentially presents riboflavin-derived metabolites to semi-invariant TRAV1.2 TCRs on MAIT cells, guiding immune surveillance of the microbial metabolome at mucosal epithelial barriers. Signature pyrimidine-based microbial antigens are generated via non-enzymatic condensation of metabolite intermediates of the riboflavin pathway with by-products arising from other metabolic pathways such as glycolysis. Typical potent antigenic metabolites are 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), products of condensation of 5-amino-6-D-ribityaminouracil (5-A-RU) with glyoxal or methylglyoxal by-products, respectively. May present microbial antigens to various TRAV1-2-negative MAIT cell subsets, providing for unique recognition of diverse microbes, including pathogens that do not synthesize riboflavin. Upon antigen recognition, elicits rapid innate-type MAIT cell activation to eliminate pathogenic microbes by directly killing infected cells. During T cell development, drives thymic selection and post-thymic terminal differentiation of MAIT cells in a process dependent on commensal microflora. Acts as an immune sensor of cancer cell metabolome. May present a tumor-specific or -associated metabolite essential for cancer cell survival to a ‘pan-cancer’ TCR consisting of TRAV38.2-DV8TRAJ31 alpha chain paired with a TRBV25.1TRBJ2.3 beta chain on a non-MAIT CD8-positive T cell clone (MC.7.G5), triggering T cell-mediated killing of a wide range of cancer cell types. Allele MR101: Presents microbial-derived metabolite 5-OP-RU to semi-invariant TRAV1.2-TRAJ33-TRBV6.1 (A-F7) TCR on MAIT cells. Presents nucleobase carbonyl adducts generated during oxidative stress. Captures M3Ade, a nucleobase adduct composed of one adenine modified by a malondialdehyde trimer, for recognition by MR1-restricted T cell clones expressing a polyclonal TCR repertoire. Displays moderate binding affinity toward tumor-enriched pyridoxal and pyridoxal 5’-phosphate antigens. Allele MR104: Presents tumor-enriched metabolite pyridoxal to pan-cancer 7.G5 TCR on T cells enabling preferential recognition of cancer cells. May act as an alloantigen.

Subunit / interactions. Heterotrimer that consists of MR1, B2M and a metabolite antigen. Major classes of metabolite ligands presented by MR1 include riboflavin-related antigens, pyrimidines and ribityl lumazines, nucleobase adducts and folate derivatives. Forms reversible covalent Schiff base complexes with microbial pyrimidine-based metabolite, which serves as a molecular switch triggering complete folding, stable association with B2M and translocation of the ternary complex from endoplasmic reticulum to the plasma membrane. Alternatively, forms non-Schiff base complexes with ribityl lumazines. On antigen-presenting cells, the ternary complex interacts with TCR on MR1-restricted T cells, predominantly represented by CD8-positive and CD4- and CD8-double negative MAIT cell subsets. Interacts with TAPBP and TAPBPL chaperones in the endoplasmic reticulum. TAPBP associated or not with MHC class I peptide loading complex binds ligand-free MR1 or MR1-B2M complex, providing for stable MR1 pools ready for metabolite antigen processing. TAPBPL interacts with MR1 in a ligand-independent way; this interaction may stabilize MR1 pool and facilitate ligand loading and dissociation. MR1-B2M heterodimer adopts a topology similar to classical MHC class I molecules, with alpha-1 and alpha-2 domains of MR1 forming the antigen-binding cleft composed of two alpha-helices resting on a floor of 7-stranded anti-parallel beta-pleated sheet. The ribityl moiety of pyrimidine-based antigens is recognized by Tyr-95 residue in the CDR3 alpha loop of the invariant TRAV1-2 TCR. Homodimerizes and does not associate with B2M.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Golgi apparatus membrane. Early endosome membrane. Late endosome membrane Cell membrane. Endoplasmic reticulum membrane Cell membrane. Endoplasmic reticulum membrane Secreted.

Tissue specificity. Ubiquitous. Low expression is detected in peripheral blood B cells, T cells, monocytes and in bronchial epithelial cells (at protein level). Expressed in plasmablasts or plasma B cells in the lamina propria of ileum, appendix and colon (at protein level). Highly expressed on a subset of CD45-positive CD3-positive thymocytes (at protein level).

Post-translational modifications. N-glycosylated.

Activity regulation. Inhibited by pterin-based metabolites such as 6-formylpterin (6-FP, a product of folic acid photodegradation). 6-FP competitively inhibits MAIT cell activation by 5-OP-RU. Modulated by commonly prescribed anti-inflammatory drug metabolites. Inhibited by salicilates such as 3-formylsalicylic and 5-formylsalicylic acids. Activated by diclofenac and/or its hydroxy metabolites.

Domain organisation. The alpha-1 domain is a structural part of antigen-binding cleft. The alpha-2 domain is a structural part of antigen-binding cleft.

Induction. (Microbial infection) Down-regulated upon infection with HHV-1/HSV-1 and HCMV herpesviruses. HSV-1 targets ligand-free MR1 to proteasomal degradation; this process requires de novo viral protein expression with US3 acting as immunoevasin partly responsible for inhibition of MR1 expression and antigen presentation in response to bacterial infection. Whereas HCMV has evolved ways to shut down both ligand-free and ligand-bound MR1 expression.

Polymorphism. Initially considered monomorphic, however recent studies show MR1 genetic diversity in human populations with allelic variants that impact antigen presentation. An analysis of a small cohort of 56 donors found six distinct alleles with MR101 and MR102 being the most frequent ones. The sequence shown is that of MR1*01.

Similarity. Belongs to the MHC class I family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q95460-1	1, MR1A	yes
Q95460-2	2
Q95460-3	3, MR1B, MR1D
Q95460-4	4, MR1C
Q95460-5	5

RefSeq proteins (9): NP_001181928, NP_001181929, NP_001181964, NP_001297142, NP_001372090, NP_001372091, NP_001372092, NP_001372093, NP_001522 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001039	MHC_I_a_a1/a2	Domain
IPR003006	Ig/MHC_CS	Conserved_site
IPR003597	Ig_C1-set	Domain
IPR007110	Ig-like_dom	Domain
IPR011161	MHC_I-like_Ag-recog	Domain
IPR011162	MHC_I/II-like_Ag-recog	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR037055	MHC_I-like_Ag-recog_sf	Homologous_superfamily
IPR050208	MHC_class-I_related	Family

Pfam: PF00129, PF07654

UniProt features (91 total): binding site 24, strand 20, sequence variant 9, helix 7, mutagenesis site 6, region of interest 5, splice variant 5, sequence conflict 3, turn 3, topological domain 2, disulfide bond 2, signal peptide 1, chain 1, transmembrane region 1, glycosylation site 1, domain 1

Structure

Experimental structures (PDB)

83 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6PUD	X-RAY DIFFRACTION	1.8
6PUG	X-RAY DIFFRACTION	1.8
6PUL	X-RAY DIFFRACTION	1.84
7ZT7	X-RAY DIFFRACTION	1.84
6PUC	X-RAY DIFFRACTION	1.85
6PUH	X-RAY DIFFRACTION	1.88
6W9U	X-RAY DIFFRACTION	1.89
4L4V	X-RAY DIFFRACTION	1.9
5U6Q	X-RAY DIFFRACTION	1.9
6PUE	X-RAY DIFFRACTION	1.9
6PUF	X-RAY DIFFRACTION	1.92
6PUJ	X-RAY DIFFRACTION	1.92
4PJE	X-RAY DIFFRACTION	1.95
6W9V	X-RAY DIFFRACTION	1.95
9O05	X-RAY DIFFRACTION	1.95
6PUI	X-RAY DIFFRACTION	1.96
6PUM	X-RAY DIFFRACTION	1.96
6PVC	X-RAY DIFFRACTION	1.96
5D7J	X-RAY DIFFRACTION	1.97
9O07	X-RAY DIFFRACTION	1.97
4L4T	X-RAY DIFFRACTION	2
4PJ5	X-RAY DIFFRACTION	2
4PJ9	X-RAY DIFFRACTION	2
4PJH	X-RAY DIFFRACTION	2
5D7I	X-RAY DIFFRACTION	2
5U16	X-RAY DIFFRACTION	2
9CGS	X-RAY DIFFRACTION	2
9O06	X-RAY DIFFRACTION	2
7ZT4	X-RAY DIFFRACTION	2.02
9BTX	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q95460-F1	87.96	0.72

Functional residue map

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

Ligand- & substrate-binding residues (24): 31; 31; 31; 31; 46; 46; 46; 65 (covalent); 65 (covalent); 65 (covalent); 65; 65 (covalent) …

Disulfide bonds (2): 120–183, 222–278

Glycosylation sites (1): 107

Mutagenesis-validated functional residues (6):

Position	Phenotype
65	associates with b2m and translocates to plasma membrane in the absence of 6-fp. refolds and adopts a stable structural c
65	fails to refold in the presence of 6-fp. impairs the association with b2m and translocation to the plasma membrane.
72	markedly decreases expression at the cell surface likely due to protein misfolding.
105	markedly decreases expression at the cell surface likely due to protein misfolding.
169	able to activate mouse mait cells (xeno-reactivity).
175	markedly decreases expression at the cell surface likely due to protein misfolding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 253 (showing top): MORF_RAGE, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_T_CELL_MEDIATED_CYTOTOXICITY, MARTINEZ_RB1_TARGETS_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE, ONKEN_UVEAL_MELANOMA_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY

GO Biological Process (10): antigen processing and presentation of peptide antigen via MHC class I (GO:0002474), positive regulation of T cell mediated cytotoxicity directed against tumor cell target (GO:0002854), immune response (GO:0006955), antigen processing and presentation of exogenous antigen (GO:0019884), T cell differentiation in thymus (GO:0033077), innate immune response (GO:0045087), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), immune system process (GO:0002376), regulation of T cell mediated immunity (GO:0002709)

GO Molecular Function (4): beta-2-microglobulin binding (GO:0030881), MHC class I receptor activity (GO:0032393), T cell receptor binding (GO:0042608), protein binding (GO:0005515)

GO Cellular Component (13): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), MHC class I protein complex (GO:0042612), extracellular region (GO:0005576), endosome (GO:0005768), Golgi apparatus (GO:0005794), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
defense response to bacterium	2
cytoplasm	2
intracellular membrane-bounded organelle	2
endosome membrane	2
cellular anatomical structure	2
antigen processing and presentation of peptide antigen	1
positive regulation of T cell mediated cytotoxicity	1
T cell mediated cytotoxicity directed against tumor cell target	1
positive regulation of T cell mediated immune response to tumor cell	1
regulation of T cell mediated cytotoxicity directed against tumor cell target	1
immune system process	1
response to stimulus	1
antigen processing and presentation	1
T cell differentiation	1
immune response	1
defense response to symbiont	1
biological_process	1
T cell mediated immunity	1
regulation of lymphocyte mediated immunity	1
regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
protein binding	1
transmembrane signaling receptor activity	1
MHC class I protein binding	1
immune receptor activity	1
signaling receptor binding	1
protein-containing complex binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
early endosome	1
late endosome	1

Protein interactions and networks

STRING

532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MR1	TRDV1	A0A1B0GX56	445
MR1	ZMYM6	O95789	370
MR1	TMEM184C	Q9NVA4	360
MR1	KIAA1614	Q5VZ46	322
MR1	SLC46A2	Q9BY10	307
MR1	KLRB1	Q12918	305
MR1	ACBD6	Q9BR61	305
MR1	BTN3A1	O00481	302
MR1	ME2	P23368	295
MR1	CD1E	P15812	291
MR1	PROCA1	Q8NCQ7	288
MR1	PRMT9	Q6P2P2	285
MR1	LRFN5	Q96NI6	276
MR1	KIF6	Q6ZMV9	263
MR1	TMEM128	Q5BJH2	261

IntAct

55 interactions, top by confidence:

A	B	Type	Score
MR1	FATE1	psi-mi:“MI:0915”(physical association)	0.560
FATE1	MR1	psi-mi:“MI:0915”(physical association)	0.560
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
ST8SIA4	FAM234B	psi-mi:“MI:0914”(association)	0.350
MPPE1	FAM234B	psi-mi:“MI:0914”(association)	0.350
ZACN	FAM234B	psi-mi:“MI:0914”(association)	0.350
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
IL17RC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
KLRC1	METTL15	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
TMEM30A	TLCD2	psi-mi:“MI:0914”(association)	0.350
DHFR2	MANBA	psi-mi:“MI:0914”(association)	0.350
HFE	PODXL	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B	ADAM10	psi-mi:“MI:0914”(association)	0.350
IFNLR1	AURKA	psi-mi:“MI:0914”(association)	0.350
NDST2	CLGN	psi-mi:“MI:0914”(association)	0.350
KLRC2	CLGN	psi-mi:“MI:0914”(association)	0.350
NHLRC3	OGG1	psi-mi:“MI:0914”(association)	0.350
PON2	ENTPD6	psi-mi:“MI:0914”(association)	0.350
HLA-E	ECEL1	psi-mi:“MI:0914”(association)	0.350
VEGFD	RPSA2	psi-mi:“MI:0914”(association)	0.350
APOM	ESYT2	psi-mi:“MI:0914”(association)	0.350
CLEC4E	ESYT2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-C	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (79): FATE1 (Two-hybrid), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-MS), MR1 (Affinity Capture-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: C1ITJ8, O19477, O35799, P01888, P01889, P01893, P01894, P01895, P01896, P01897, P01898, P01899, P01900, P01901, P01902, P03991, P04223, P04439, P06126, P06140, P06339, P10321, P13747, P13748, P13749, P13750, P13751, P13752, P13753, P13765, P14426, P14427, P14428, P14429, P14430, P14431, P14432, P15464, P15978, P15979

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 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
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	8	13.4×	1e-05
Interferon gamma signaling	5	12.1×	2e-03
SARS-CoV-2 activates/modulates innate and adaptive immune responses	5	8.6×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of T cell mediated cytotoxicity	7	51.1×	3e-08
adaptive immune response	8	9.6×	1e-04
immune response	9	6.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1078 predictions. Top by Δscore:

Variant	Effect	Δscore
1:181034075:G:GG	donor_gain	1.0000
1:181050282:AACAG:A	donor_loss	1.0000
1:181050285:AGGTA:A	donor_loss	1.0000
1:181050286:GG:G	donor_loss	1.0000
1:181050287:GTA:G	donor_loss	1.0000
1:181050288:T:A	donor_loss	1.0000
1:181034070:TTCCC:T	donor_gain	0.9900
1:181034071:TCCCG:T	donor_loss	0.9900
1:181034073:CC:C	donor_gain	0.9900
1:181034073:CCGTG:C	donor_loss	0.9900
1:181034074:CG:C	donor_loss	0.9900
1:181034076:TGAG:T	donor_loss	0.9900
1:181034077:G:GT	donor_loss	0.9900
1:181034078:AGT:A	donor_loss	0.9900
1:181049308:CTCAG:C	donor_loss	0.9900
1:181049309:TCAGG:T	donor_loss	0.9900
1:181049310:CAGG:C	donor_loss	0.9900
1:181049311:AG:A	donor_loss	0.9900
1:181049312:GG:G	donor_loss	0.9900
1:181049313:GTGT:G	donor_loss	0.9900
1:181049314:T:G	donor_loss	0.9900
1:181050008:CAG:C	acceptor_loss	0.9900
1:181050009:AG:A	acceptor_gain	0.9900
1:181050010:G:GA	acceptor_loss	0.9900
1:181050010:GG:G	acceptor_gain	0.9900
1:181050010:GGGT:G	acceptor_gain	0.9900
1:181034072:CCC:C	donor_gain	0.9800
1:181034079:G:C	donor_loss	0.9800
1:181049046:TTCCA:T	acceptor_loss	0.9800
1:181049047:TCCAG:T	acceptor_loss	0.9800

AlphaMissense

2229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:181052309:T:C	F227L	0.997
1:181052311:T:A	F227L	0.997
1:181052311:T:G	F227L	0.997
1:181049114:T:C	F44L	0.994
1:181049116:T:A	F44L	0.994
1:181049116:T:G	F44L	0.994
1:181052310:T:C	F227S	0.990
1:181052294:T:A	C222S	0.987
1:181052295:G:C	C222S	0.987
1:181052336:T:A	W236R	0.985
1:181052336:T:C	W236R	0.985
1:181052310:T:G	F227C	0.984
1:181049120:T:C	S46P	0.983
1:181049197:G:C	W71C	0.983
1:181049197:G:T	W71C	0.983
1:181052295:G:A	C222Y	0.982
1:181050040:T:A	C120S	0.981
1:181050041:G:C	C120S	0.981
1:181050133:T:A	W151R	0.981
1:181050133:T:C	W151R	0.981
1:181052462:T:A	C278S	0.981
1:181052463:G:C	C278S	0.981
1:181049195:T:A	W71R	0.980
1:181049195:T:C	W71R	0.980
1:181049064:T:C	L27P	0.979
1:181049115:T:C	F44S	0.979
1:181049227:G:C	W81C	0.978
1:181049227:G:T	W81C	0.978
1:181050085:G:C	A135P	0.978
1:181050242:T:C	L187P	0.978

dbSNP variants (sampled 300 via entrez): RS1000132392 (1:181047021 G>C,T), RS1000140141 (1:181054175 G>A), RS1000201608 (1:181056693 G>A), RS1000460889 (1:181058763 A>T), RS1000492004 (1:181059062 G>T), RS1000503132 (1:181039920 A>G), RS1000511820 (1:181053770 A>T), RS1000559080 (1:181035118 T>C), RS1000617318 (1:181046450 C>T), RS1000954141 (1:181032410 A>G,T), RS1001001907 (1:181033977 T>C), RS1001243780 (1:181055660 T>C), RS1001467670 (1:181054591 C>T), RS1001490038 (1:181046067 C>G,T), RS1001498651 (1:181054837 G>A)

Disease associations

OMIM: gene MIM:600764 | disease phenotypes: MIM:300755

GenCC curated gene-disease

Mondo (1): immunodeficiency disease (MONDO:0021094)

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003262_514	Post bronchodilator FEV1	2.000000e-06
GCST010697_5	Cortical surface area (min-P)	4.000000e-11
GCST010698_73	Subcortical volume (min-P)	1.000000e-13
GCST010699_38	Brain morphology (min-P)	1.000000e-08
GCST010700_67	Cortical thickness (MOSTest)	4.000000e-09
GCST010701_105	Cortical surface area (MOSTest)	3.000000e-12
GCST010702_28	Subcortical volume (MOSTest)	6.000000e-11
GCST010703_252	Brain morphology (MOSTest)	4.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465401 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, increases expression, increases methylation	6
Benzo(a)pyrene	decreases methylation, increases expression	5
Air Pollutants	decreases expression, affects expression, increases abundance, increases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
Cisplatin	affects cotreatment, increases expression	2
Etoposide	affects expression, increases expression	2
Methyl Methanesulfonate	increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
sodium arsenite	increases expression	1
iopromide	affects expression	1
repaglinide	affects expression	1
CGP 52608	increases reaction, affects binding	1
corosolic acid	increases expression	1
rofecoxib	affects expression	1
monomethylarsonous acid	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
jinfukang	increases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Gefitinib	affects expression	1
Resveratrol	increases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5324830	Binding	Binding affinity to N-terminal HiBit-tagged human beta2m/MR1 in human HEK293 cells assessed as increase in MR1 surface expression level by measuring increase in luminescence intensity at 10 uM using furimazine as substrate preincubated for	Establishment of an MR1 Presentation Reporter Screening System and Identification of Phenylpropanoid Derivatives as MR1 Ligands. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	PHASE3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	PHASE3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	PHASE3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	PHASE3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	PHASE3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)
NCT00478231	PHASE3	COMPLETED	Multicenter, Safety Study Of Maraviroc
NCT00523211	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04405AM5)
NCT00698334	PHASE3	COMPLETED	Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
NCT00966160	PHASE3	COMPLETED	CD4 Cell Recovery in HIV-1 Patients Comparing 2 Treatment Regimes
NCT01363011	PHASE3	COMPLETED	Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
NCT01440569	PHASE3	COMPLETED	Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults
NCT01475838	PHASE3	COMPLETED	Study to Evaluate Switching From Regimens Consisting of a Ritonavir-boosted Protease Inhibitor Plus Emtricitabine/Tenofovir Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients