HLA-E

HLA-E belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail.

HLA-E

Non-classical major histocompatibility class Ib molecule involved in immune self-nonself discrimination. In complex with B2M/beta-2-microglobulin binds nonamer self-peptides derived from the signal sequence of classical MHC class Ia molecules (VL9 peptides) (PubMed:9754572, PubMed:18083576, PubMed:18339401).

Peptide-bound HLA-E-B2M heterotrimeric complex primarily functions as a ligand for natural killer (NK) cell inhibitory receptor KLRD1-KLRC1, enabling NK cells to monitor the expression of other MHC class I molecules in healthy cells and to tolerate self (PubMed:9754572, PubMed:9486650, PubMed:17179229, PubMed:18083576).

Upon cellular stress, preferentially binds signal sequence-derived peptides from stress-induced chaperones and is no longer recognized by NK cell inhibitory receptor KLRD1-KLRC1, resulting in impaired protection from NK cells (PubMed:12461076).

Binds signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules and acts as a ligand for NK cell activating receptor KLRD1-KLRC2, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy (PubMed:9754572, PubMed:30134159).

Besides self-peptides, can also bind and present pathogen-derived peptides conformationally similar to VL9 peptides to alpha-beta T cell receptor (TCR) on unconventional CD8+ cytotoxic T cells, ultimately triggering antimicrobial immune response (PubMed:16474394, PubMed:30087334).

(Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells.

(Microbial infection) May bind HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition.

(Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells (PubMed:32859121).

Binds SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance (PubMed:32859121).

Adaptive immune response Source: UniProtKB
Antibacterial humoral response Source: UniProtKB
Antigen processing and presentation of endogenous peptide antigen via MHC class Ib Source: UniProtKB
Antigen processing and presentation of exogenous peptide antigen via MHC class Ib Source: UniProtKB
Antigen processing and presentation of peptide antigen via MHC class I Source: UniProtKB-KW
CD8-positive, alpha-beta T cell activation Source: UniProtKB
Defense response to Gram-positive bacterium Source: UniProtKB
Innate immune response Source: UniProtKB-KW
Natural killer cell tolerance induction Source: UniProtKB
Negative regulation of natural killer cell mediated cytotoxicity Source: UniProtKB
Positive regulation of antibody-dependent cellular cytotoxicity Source: UniProtKB
Positive regulation of CD8-positive, alpha-beta T cell activation Source: UniProtKB
Positive regulation of CD8-positive, alpha-beta T cell proliferation Source: UniProtKB
Positive regulation of immunoglobulin production Source: UniProtKB
Positive regulation of interleukin-13 production Source: UniProtKB
Positive regulation of interleukin-4 production Source: UniProtKB
Positive regulation of natural killer cell cytokine production Source: UniProtKB
Positive regulation of natural killer cell mediated cytotoxicity Source: UniProtKB
Positive regulation of natural killer cell mediated immunity Source: UniProtKB
Positive regulation of natural killer cell proliferation Source: UniProtKB
Positive regulation of T cell mediated cytotoxicity Source: UniProtKB
Positive regulation of TRAIL production Source: UniProtKB
Positive regulation of tumor necrosis factor production Source: UniProtKB
Protection from natural killer cell mediated cytotoxicity Source: UniProtKB
Regulation of natural killer cell mediated immunity Source: UniProtKB

Golgi apparatus membrane; Cell membrane; Secreted

Extracellular: 22-305
Helical: 306-329
Cytoplasmic: 330-358

N-glycosylated.
The soluble form (sHLA-E) can be partly produced by proteolytic cleavage at the cell surface (shedding) by a matrix metalloproteinase. Alternative splicing is also suggested as a mechanism for generation of sHLA-E, although it remains to be proved.