HLA-E

Major histocompatibility complex, class I, E
PDB rendering based on 1kpr.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1KPR​, 1KTL​, 1MHE​, 2ESV​, 3AM8​, 3BZE​, 3BZF​, 3CDG​, 3CII​
Identifiers
Symbols	HLA-E ; EA1.2; EA2.1; HLA-6.2; MHC; QA1
External IDs	OMIM: 143010 MGI: 95957 HomoloGene: 134018 GeneCards: HLA-E Gene
Gene ontology Molecular function • receptor binding • beta-2-microglobulin binding • MHC class I protein binding • peptide antigen binding • natural killer cell lectin-like receptor binding Cellular component • Golgi membrane • plasma membrane • cell surface • ER to Golgi transport vesicle membrane • phagocytic vesicle membrane • early endosome membrane • MHC class Ib protein complex • MHC class I protein complex • extracellular exosome • integral component of lumenal side of endoplasmic reticulum membrane Biological process • positive regulation of T cell mediated cytotoxicity • adaptive immune response • antigen processing and presentation of peptide antigen via MHC class I • antigen processing and presentation of endogenous peptide antigen via MHC class Ib • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent • regulation of natural killer cell mediated immunity • positive regulation of natural killer cell mediated immunity • cytokine-mediated signaling pathway • antibacterial humoral response • positive regulation of interleukin-13 production • positive regulation of interleukin-4 production • positive regulation of TRAIL production • positive regulation of tumor necrosis factor production • CD8-positive, alpha-beta T cell activation • protection from natural killer cell mediated cytotoxicity • antigen processing and presentation of exogenous peptide antigen via MHC class I • innate immune response • regulation of immune response • defense response to Gram-positive bacterium • positive regulation of immunoglobulin secretion • interferon-gamma-mediated signaling pathway • type I interferon signaling pathway • positive regulation of CD8-positive, alpha-beta T cell proliferation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3133	15040
Ensembl	ENSG00000204592	ENSMUSG00000067212
UniProt	P13747	P06339
RefSeq (mRNA)	NM_005516	NM_010398
RefSeq (protein)	NP_005507	NP_034528
Location (UCSC)	Chr 6: 30.49 – 30.49 Mb	Chr 17: 36.03 – 36.03 Mb
PubMed search

HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene.^[1] The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called Qa-1b.

Structure

Like other MHC class I molecules, HLA-E is a heterodimer consisting of an α heavy chain and a light chain (β-2 microglobulin). The heavy chain is approximately 45 kDa and anchored in the membrane. The HLA-E gene contains 8 exons. Exon one encodes the signal peptide, exons 2 and 3 encode the α1 and α2 domains, which both bind the peptide, exon 4 encodes the α3 domain, exon 5 encodes the transmembrane domain, and exons 6 and 7 encode the cytoplasmic tail.^[2]

Function

HLA-E has a very specialized role in cell recognition by natural killer cells (NK cells).^[3] HLA-E binds a restricted subset of peptides derived from signal peptides of classical MHC class I molecules, namely HLA-A, B, C, G.^[4] These peptides are released from the membrane of the endoplasmic reticulum (ER) by the signal peptide peptidase and trimmed by the cytosolic proteasome.^[5][6] Upon transport into the ER lumen by the transporter associated with antigen processing (TAP), these peptides bind to a peptide binding groove on the HLA-E molecule.^[7] This allows HLA-E to assemble correctly and to be expressed on the cell surface. NK cells recognize the HLA-E+peptide complex using the heterodimeric inhibitory receptor CD94/NKG2A/B/C.^[3] When CD94/NKG2A or CD94/NKG2B is engaged, it produces an inhibitory effect on the cytotoxic activity of the NK cell to prevent cell lysis. However, binding of HLA-E to CD94/NKG2C results in NK cell activation. This interaction has been shown to trigger expansion of NK cell subsets in antiviral responses.^[8]

References

1. Mizuno S, Trapani JA, Koller BH, Dupont B, Yang SY (Jun 1988). "Isolation and nucleotide sequence of a cDNA clone encoding a novel HLA class I gene". Journal of Immunology 140 (11): 4024–30. PMID 3131426.
2. "Entrez Gene: HLA-E major histocompatibility complex, class I, E".
3. Braud VM, Allan DS, O'Callaghan CA, Söderström K, D'Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ (Feb 1998). "HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C". Nature 391 (6669): 795–9. doi:10.1038/35869. PMID 9486650.
4. Braud V, Jones EY, McMichael A (May 1997). "The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9". European Journal of Immunology 27 (5): 1164–9. doi:10.1002/eji.1830270517. PMID 9174606.
5. Lemberg MK, Bland FA, Weihofen A, Braud VM, Martoglio B (Dec 2001). "Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes". Journal of Immunology 167 (11): 6441–6. doi:10.4049/jimmunol.167.11.6441. PMID 11714810.
6. Bland FA, Lemberg MK, McMichael AJ, Martoglio B, Braud VM (Sep 2003). "Requirement of the proteasome for the trimming of signal peptide-derived epitopes presented by the nonclassical major histocompatibility complex class I molecule HLA-E". The Journal of Biological Chemistry 278 (36): 33747–52. doi:10.1074/jbc.M305593200. PMID 12821659.
7. Braud VM, Allan DS, Wilson D, McMichael AJ (Jan 1998). "TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide". Current Biology 8 (1): 1–10. doi:10.1016/S0960-9822(98)70014-4. PMID 9427624.
8. Rölle A, Pollmann J, Ewen EM, Le VT, Halenius A, Hengel H, Cerwenka A (Dec 2014). "IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion". The Journal of Clinical Investigation 124 (12): 5305–16. doi:10.1172/JCI77440. PMID 25384219.

Further reading

• Kuby Immunology, 6th edition, by Thomas J. Kindt, Richard A. Goldsby,and Barbara A.Kuby W.H. Freeman and Company,New York
• Moretta L, Bottino C, Pende D, Mingari MC, Biassoni R, Moretta A (May 2002). "Human natural killer cells: their origin, receptors and function". European Journal of Immunology 32 (5): 1205–11. doi:10.1002/1521-4141(200205)32:5<1205::AID-IMMU1205>3.0.CO;2-Y. PMID 11981807.
• Jensen PE, Sullivan BA, Reed-Loisel LM, Weber DA (Jun 2004). "Qa-1, a nonclassical class I histocompatibility molecule with roles in innate and adaptive immunity". Immunologic Research 29 (1-3): 81–92. doi:10.1385/IR:29:1-3:081. PMID 15181272.