UniProt functional annotation for Q95460



	UniProt functional annotation for Q95460

UniProt code: Q95460.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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 (PubMed:23051753, PubMed:26795251, PubMed:12794138, PubMed:19416870, PubMed:22692454, PubMed:23846752). 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 (PubMed:26795251, PubMed:24695216, PubMed:20581831). 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 (PubMed:24695216). 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 (PubMed:27527800, PubMed:31113973). Upon antigen recognition, elicits rapid innate-type MAIT cell activation to eliminate pathogenic microbes by directly killing infected cells (PubMed:24695216, PubMed:27527800, PubMed:23846752). During T cell development, drives thymic selection and post-thymic terminal differentiation of MAIT cells in a process dependent on commensal microflora (By similarity). Acts as an immune sensor of cancer cell metabolome (PubMed:31959982). May present a tumor-specific or -associated metabolite essential for cancer cell survival to a pan-cancer TCR consisting of TRAV38.2-DV8*TRAJ31 alpha chain paired with a TRBV25.1*TRBJ2.3 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 (PubMed:31959982). {ECO:0000250|UniProtKB:Q8HWB0, ECO:0000269|PubMed:12794138, ECO:0000269|PubMed:19416870, ECO:0000269|PubMed:20581831, ECO:0000269|PubMed:22692454, ECO:0000269|PubMed:23051753, ECO:0000269|PubMed:23846752, ECO:0000269|PubMed:24695216, ECO:0000269|PubMed:26795251, ECO:0000269|PubMed:27527800, ECO:0000269|PubMed:31113973, ECO:0000269|PubMed:31959982}.

Activity regulation: Usually 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 (PubMed:28166217). 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 (PubMed:28166217). {ECO:0000269|PubMed:28166217}.

Subunit: Heterotrimer that consists of MR1, B2M and a metabolite antigen (PubMed:27043408, PubMed:23051753, PubMed:23846752, PubMed:24695216). Forms reversible covalent Schiff base complexes with the microbial 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 (PubMed:27043408, PubMed:23051753, PubMed:23846752, PubMed:24695216). On antigen-presenting cells, the ternary complex interacts with TCR on CD8-positive T cells (PubMed:23846752, PubMed:24695216, PubMed:26795251). The molecular machinery involved in antigen processing remains unknown, but appears to be TAP1-TAP2 and proteasome- independent. Structurally, 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 (PubMed:23846752, PubMed:24695216, PubMed:26795251). The ribityl moiety of pyrimidine-based antigens is recognized by Tyr-95 residue in the CDR3 alpha loop of the invariant TRAV1-2 TCR (PubMed:23846752, PubMed:24695216, PubMed:26795251). {ECO:0000269|PubMed:23051753, ECO:0000269|PubMed:23846752, ECO:0000269|PubMed:24695216, ECO:0000269|PubMed:26795251, ECO:0000269|PubMed:27043408}.

Subunit: [Isoform 3]: Homodimerizes and does not associate with B2M. {ECO:0000269|PubMed:23457030, ECO:0000305|PubMed:20581831}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:12794138, ECO:0000269|PubMed:18068122, ECO:0000269|PubMed:27043408}; Single-pass type I membrane protein. Endoplasmic reticulum membrane {ECO:0000269|PubMed:18068122, ECO:0000269|PubMed:27043408}; Single-pass type I membrane protein {ECO:0000255}. Golgi apparatus membrane {ECO:0000269|PubMed:18068122}; Single-pass type I membrane protein {ECO:0000255}. Early endosome membrane {ECO:0000269|PubMed:27043408}; Single-pass type I membrane protein {ECO:0000255}. Late endosome membrane {ECO:0000269|PubMed:18068122, ECO:0000269|PubMed:27043408}; Single-pass type I membrane protein {ECO:0000255}. Note=In the absence of antigen remains within the endoplasmic reticulum where it acts as a metabolite sensor. Antigen binding triggers trafficking of the ternary complex to the plasma membrane. After presentation, most of these complexes are rapidly internalized and degraded via endocytosis. A small subset recycles via endosomes back to the plasma membrane and may thus acquire and present new antigens that do not efficiently reach the endoplasmic reticulum. {ECO:0000269|PubMed:27043408}.

Subcellular location: [Isoform 1]: Cell membrane {ECO:0000269|PubMed:23457030}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:23457030}; Single-pass membrane protein {ECO:0000255}.

Subcellular location: [Isoform 3]: Cell membrane {ECO:0000269|PubMed:23457030}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:23457030}; Single-pass membrane protein {ECO:0000255}. Note=The larger proportion remains in the ER in an immature state. The subset that reach cell surface does it through a B2M-independent pathway. {ECO:0000269|PubMed:23457030}.

Subcellular location: [Isoform 4]: Secreted {ECO:0000303|PubMed:9780177}.

Tissue specificity: Ubiquitous (PubMed:7624800, PubMed:9780177). Low expression is detected in peripheral blood B cells, T cells, monocytes and in bronchial epithelial cells (at protein level) (PubMed:27043408). Expressed in plasmablasts or plasma B cells in the lamina propria of ileum, appendix and colon (at protein level) (PubMed:19760593). Highly expressed on a subset of CD45-positive CD3-positive thymocytes (at protein level) (PubMed:22692454). {ECO:0000269|PubMed:19760593, ECO:0000269|PubMed:22692454, ECO:0000269|PubMed:27043408, ECO:0000269|PubMed:7624800, ECO:0000269|PubMed:9780177}.

Domain: The alpha-1 domain is a structural part of antigen-binding cleft. {ECO:0000269|PubMed:23846752, ECO:0000269|PubMed:24695216, ECO:0000269|PubMed:26795251}.

Domain: The alpha-2 domain is a structural part of antigen-binding cleft. {ECO:0000269|PubMed:24695216, ECO:0000269|PubMed:26795251}.

Ptm: N-glycosylated. {ECO:0000269|PubMed:12794138, ECO:0000269|PubMed:27043408}.

Polymorphism: Several individuals from different ethnic background were analyzed for polymorphism. MR1 was identical in all individuals analyzed, except one. MR1 is not polymorphic. {ECO:0000269|PubMed:11019920}.

Similarity: Belongs to the MHC class I family. {ECO:0000305}.

Sequence caution: Sequence=AAD01443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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 (PubMed:23051753, PubMed:26795251, PubMed:12794138, PubMed:19416870, PubMed:22692454, PubMed:23846752). 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 (PubMed:26795251, PubMed:24695216, PubMed:20581831). 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 (PubMed:24695216). 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 (PubMed:27527800, PubMed:31113973). Upon antigen recognition, elicits rapid innate-type MAIT cell activation to eliminate pathogenic microbes by directly killing infected cells (PubMed:24695216, PubMed:27527800, PubMed:23846752). During T cell development, drives thymic selection and post-thymic terminal differentiation of MAIT cells in a process dependent on commensal microflora (By similarity). Acts as an immune sensor of cancer cell metabolome (PubMed:31959982). 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 (PubMed:31959982). {ECO:0000250\|UniProtKB:Q8HWB0, ECO:0000269\|PubMed:12794138, ECO:0000269\|PubMed:19416870, ECO:0000269\|PubMed:20581831, ECO:0000269\|PubMed:22692454, ECO:0000269\|PubMed:23051753, ECO:0000269\|PubMed:23846752, ECO:0000269\|PubMed:24695216, ECO:0000269\|PubMed:26795251, ECO:0000269\|PubMed:27527800, ECO:0000269\|PubMed:31113973, ECO:0000269\|PubMed:31959982}.


Activity regulation:		Usually 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 (PubMed:28166217). 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 (PubMed:28166217). {ECO:0000269\|PubMed:28166217}.
Subunit:		Heterotrimer that consists of MR1, B2M and a metabolite antigen (PubMed:27043408, PubMed:23051753, PubMed:23846752, PubMed:24695216). Forms reversible covalent Schiff base complexes with the microbial 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 (PubMed:27043408, PubMed:23051753, PubMed:23846752, PubMed:24695216). On antigen-presenting cells, the ternary complex interacts with TCR on CD8-positive T cells (PubMed:23846752, PubMed:24695216, PubMed:26795251). The molecular machinery involved in antigen processing remains unknown, but appears to be TAP1-TAP2 and proteasome- independent. Structurally, 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 (PubMed:23846752, PubMed:24695216, PubMed:26795251). The ribityl moiety of pyrimidine-based antigens is recognized by Tyr-95 residue in the CDR3 alpha loop of the invariant TRAV1-2 TCR (PubMed:23846752, PubMed:24695216, PubMed:26795251). {ECO:0000269\|PubMed:23051753, ECO:0000269\|PubMed:23846752, ECO:0000269\|PubMed:24695216, ECO:0000269\|PubMed:26795251, ECO:0000269\|PubMed:27043408}.
Subunit:		[Isoform 3]: Homodimerizes and does not associate with B2M. {ECO:0000269\|PubMed:23457030, ECO:0000305\|PubMed:20581831}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:12794138, ECO:0000269\|PubMed:18068122, ECO:0000269\|PubMed:27043408}; Single-pass type I membrane protein. Endoplasmic reticulum membrane {ECO:0000269\|PubMed:18068122, ECO:0000269\|PubMed:27043408}; Single-pass type I membrane protein {ECO:0000255}. Golgi apparatus membrane {ECO:0000269\|PubMed:18068122}; Single-pass type I membrane protein {ECO:0000255}. Early endosome membrane {ECO:0000269\|PubMed:27043408}; Single-pass type I membrane protein {ECO:0000255}. Late endosome membrane {ECO:0000269\|PubMed:18068122, ECO:0000269\|PubMed:27043408}; Single-pass type I membrane protein {ECO:0000255}. Note=In the absence of antigen remains within the endoplasmic reticulum where it acts as a metabolite sensor. Antigen binding triggers trafficking of the ternary complex to the plasma membrane. After presentation, most of these complexes are rapidly internalized and degraded via endocytosis. A small subset recycles via endosomes back to the plasma membrane and may thus acquire and present new antigens that do not efficiently reach the endoplasmic reticulum. {ECO:0000269\|PubMed:27043408}.
Subcellular location:		[Isoform 1]: Cell membrane {ECO:0000269\|PubMed:23457030}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269\|PubMed:23457030}; Single-pass membrane protein {ECO:0000255}.
Subcellular location:		[Isoform 3]: Cell membrane {ECO:0000269\|PubMed:23457030}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269\|PubMed:23457030}; Single-pass membrane protein {ECO:0000255}. Note=The larger proportion remains in the ER in an immature state. The subset that reach cell surface does it through a B2M-independent pathway. {ECO:0000269\|PubMed:23457030}.
Subcellular location:		[Isoform 4]: Secreted {ECO:0000303\|PubMed:9780177}.
Tissue specificity:		Ubiquitous (PubMed:7624800, PubMed:9780177). Low expression is detected in peripheral blood B cells, T cells, monocytes and in bronchial epithelial cells (at protein level) (PubMed:27043408). Expressed in plasmablasts or plasma B cells in the lamina propria of ileum, appendix and colon (at protein level) (PubMed:19760593). Highly expressed on a subset of CD45-positive CD3-positive thymocytes (at protein level) (PubMed:22692454). {ECO:0000269\|PubMed:19760593, ECO:0000269\|PubMed:22692454, ECO:0000269\|PubMed:27043408, ECO:0000269\|PubMed:7624800, ECO:0000269\|PubMed:9780177}.
Domain:		The alpha-1 domain is a structural part of antigen-binding cleft. {ECO:0000269\|PubMed:23846752, ECO:0000269\|PubMed:24695216, ECO:0000269\|PubMed:26795251}.
Domain:		The alpha-2 domain is a structural part of antigen-binding cleft. {ECO:0000269\|PubMed:24695216, ECO:0000269\|PubMed:26795251}.
Ptm:		N-glycosylated. {ECO:0000269\|PubMed:12794138, ECO:0000269\|PubMed:27043408}.
Polymorphism:		Several individuals from different ethnic background were analyzed for polymorphism. MR1 was identical in all individuals analyzed, except one. MR1 is not polymorphic. {ECO:0000269\|PubMed:11019920}.
Similarity:		Belongs to the MHC class I family. {ECO:0000305}.
Sequence caution:		Sequence=AAD01443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};