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== Function ==
== Function ==


HLA-E has a very specialized role in cell recognition by [[natural killer cells]] (NK cells).<ref name="pmid9486650">{{cite journal | vauthors = 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 | title = HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C | journal = Nature | volume = 391 | issue = 6669 | pages = 795–9 | date = Feb 1998 | pmid = 9486650 | doi = 10.1038/35869 }}</ref> HLA-E binds a restricted subset of peptides derived from [[signal peptides]] of classical MHC class I molecules, namely HLA-A, B, C, G.<ref name="pmid9174606">{{cite journal | vauthors = Braud V, Jones EY, McMichael A | title = The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9 | journal = European Journal of Immunology | volume = 27 | issue = 5 | pages = 1164–9  | date = May 1997 | pmid = 9174606 | doi = 10.1002/eji.1830270517 }}</ref> These peptides are released from the membrane of the [[endoplasmic reticulum]] (ER) by the [[signal peptide peptidase]] and trimmed by the cytosolic [[proteasome]].<ref name="pmid11714810">{{cite journal | vauthors = Lemberg MK, Bland FA, Weihofen A, Braud VM, Martoglio B | title = Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes | journal = Journal of Immunology | volume = 167 | issue = 11 | pages = 6441–6 | date = Dec 2001 | pmid = 11714810 | doi = 10.4049/jimmunol.167.11.6441 }}</ref><ref name="pmid12821659">{{cite journal | vauthors = Bland FA, Lemberg MK, McMichael AJ, Martoglio B, Braud VM | title = Requirement of the proteasome for the trimming of signal peptide-derived epitopes presented by the nonclassical major histocompatibility complex class I molecule HLA-E | journal = The Journal of Biological Chemistry | volume = 278 | issue = 36 | pages = 33747–52 | date = Sep 2003 | pmid = 12821659 | doi = 10.1074/jbc.M305593200 }}</ref> 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.<ref name="pmid9427624">{{cite journal | vauthors = Braud VM, Allan DS, Wilson D, McMichael AJ | title = TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide | journal = Current Biology | volume = 8 | issue = 1 | pages = 1–10  | date = Jan 1998 | pmid = 9427624 | doi = 10.1016/S0960-9822(98)70014-4 }}</ref> This allows HLA-E to assemble correctly and to be expressed on the [[cell membrane|cell surface]]. NK cells recognize the HLA-E+peptide complex using the heterodimeric inhibitory receptor [[CD94]]/[[NKG2]]A/B/C.<ref name="pmid9486650"/> 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.<ref>{{cite journal | vauthors = Rölle A, Pollmann J, Ewen EM, Le VT, Halenius A, Hengel H, Cerwenka A | title = IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion | journal = The Journal of Clinical Investigation | volume = 124 | issue = 12 | pages = 5305–16 | date = Dec 2014 | pmid = 25384219 | doi = 10.1172/JCI77440 | pmc=4348979}}</ref>
HLA-E has a very specialized role in cell recognition by [[natural killer cells]] (NK cells).<ref name="pmid9486650">{{cite journal | vauthors = 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 | title = HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C | journal = Nature | volume = 391 | issue = 6669 | pages = 795–9 | date = Feb 1998 | pmid = 9486650 | doi = 10.1038/35869 }}</ref> HLA-E binds a restricted subset of peptides derived from [[signal peptides]] of classical MHC class I molecules, namely HLA-A, B, C, G.<ref name="pmid9174606">{{cite journal | vauthors = Braud V, Jones EY, McMichael A | title = The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9 | journal = European Journal of Immunology | volume = 27 | issue = 5 | pages = 1164–9  | date = May 1997 | pmid = 9174606 | doi = 10.1002/eji.1830270517 }}</ref> These peptides are released from the membrane of the [[endoplasmic reticulum]] (ER) by the [[signal peptide peptidase]] and trimmed by the cytosolic [[proteasome]].<ref name="pmid11714810">{{cite journal | vauthors = Lemberg MK, Bland FA, Weihofen A, Braud VM, Martoglio B | title = Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes | journal = Journal of Immunology | volume = 167 | issue = 11 | pages = 6441–6 | date = Dec 2001 | pmid = 11714810 | doi = 10.4049/jimmunol.167.11.6441 }}</ref><ref name="pmid12821659">{{cite journal | vauthors = Bland FA, Lemberg MK, McMichael AJ, Martoglio B, Braud VM | title = Requirement of the proteasome for the trimming of signal peptide-derived epitopes presented by the nonclassical major histocompatibility complex class I molecule HLA-E | journal = The Journal of Biological Chemistry | volume = 278 | issue = 36 | pages = 33747–52 | date = Sep 2003 | pmid = 12821659 | doi = 10.1074/jbc.M305593200 }}</ref> 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.<ref name="pmid9427624">{{cite journal | vauthors = Braud VM, Allan DS, Wilson D, McMichael AJ | title = TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide | journal = Current Biology | volume = 8 | issue = 1 | pages = 1–10  | date = Jan 1998 | pmid = 9427624 | doi = 10.1016/S0960-9822(98)70014-4 }}</ref> This allows HLA-E to assemble correctly and to be expressed on the [[cell membrane|cell surface]]. NK cells recognize the HLA-E+peptide complex using the heterodimeric receptor [[CD94]]/[[NKG2]]A/B/C.<ref name="pmid9486650"/> 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.<ref>{{cite journal | vauthors = Rölle A, Pollmann J, Ewen EM, Le VT, Halenius A, Hengel H, Cerwenka A | title = IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion | journal = The Journal of Clinical Investigation | volume = 124 | issue = 12 | pages = 5305–16 | date = Dec 2014 | pmid = 25384219 | doi = 10.1172/JCI77440 | pmc=4348979}}</ref>


== References ==
== References ==

Latest revision as of 08:58, 31 December 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
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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, officially known as H2-T23.

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 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. ↑ 3.0 3.1 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. PMC 4348979. 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.
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