| MHC class I | |
|---|---|
 Schematic representation of MHC class I | |
| Identifiers | |
| Symbol | MHC class I |
| Membranome | 63 |
MHC class I molecules are one of two primary classes ofmajor histocompatibility complex (MHC) molecules (the other beingMHC class II) and are found on thecell surface of allnucleated cells in the bodies ofvertebrates.[1][2] They also occur onplatelets, but not onred blood cells. Their function is to display peptide fragments of proteins from within the cell tocytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules presentpeptides derived fromcytosolic proteins, the pathway of MHC class I presentation is often calledcytosolic orendogenous pathway.[3]
In humans, theHLAs corresponding to MHC class I areHLA-A,HLA-B, andHLA-C.
Class I MHC molecules bindpeptides generated mainly from the degradation of cytosolic proteins by theproteasome. The MHC I: peptide complex is then inserted via the endoplasmic reticulum into the external plasma membrane of the cell. The epitope peptide is bound on extracellular parts of the class I MHC molecule. Thus, the function of the class I MHC is to display intracellular proteins tocytotoxic T cells (CTLs). However, class I MHC can also present peptides generated from exogenous proteins, in a process known ascross-presentation.
A normal cell will display peptides from normal cellular protein turnover on its class I MHC, and CTLs will not be activated in response to them due to central and peripheral tolerance mechanisms. When a cell expresses foreign proteins, such as after viral infection, a fraction of the class I MHC will display these peptides on the cell surface. Consequently, CTLs specific for the MHC:peptide complex will recognize and kill presenting cells.
Alternatively, class I MHC itself can serve as an inhibitory ligand fornatural killer cells (NKs). Reduction in the normal levels of surface class I MHC, a mechanism employed by some viruses[4] and certain tumors to evade CTL responses, activates NK cell killing.
Paired-immunoglobulin-like receptor B (PirB), an MHCI-binding receptor, is involved in the regulation of visualplasticity.[5] PirB is expressed in thecentral nervous system and diminishesocular dominanceplasticity in the developmentalcritical period and adulthood.[5] When the function of PirB was abolished in mutant mice,ocular dominanceplasticity became more pronounced at all ages.[5] PirB loss of function mutant mice also exhibited enhancedplasticity after monocular deprivation during thecritical period.[5] These results suggest that PirB may be involved in the modulation ofsynaptic plasticity in thevisual cortex.
MHC class I molecules are heterodimers that consist of two polypeptide chains, α andβ2-microglobulin (B2M). The two chains are linked noncovalently via interaction of B2M and the α3 domain. Only the α chain is polymorphic and encoded by aHLA gene, while the B2M subunit is not polymorphic and encoded by thebeta-2 microglobulin gene. The α3 domain is plasma membrane-spanning and interacts with theCD8 co-receptor ofT-cells. The α3-CD8 interaction holds the MHC I molecule in place while theT cell receptor (TCR) on the surface of the cytotoxic T cell binds its α1-α2 heterodimer ligand, and checks the coupled peptide for antigenicity. The α1 and α2 domains fold to make up a groove for peptides to bind. MHC class I molecules bind peptides that are predominantly 8-10 amino acid in length (Parham 87), but the binding of longer peptides have also been reported.[6]
While a high-affinity peptide and the B2M subunit are normally required to maintain a stableternary complex between the peptide, MHC I, and B2M, under subphysiological temperatures, stable, peptide-deficient MHC I/B2Mheterodimers have been observed.[7][8] Synthetic stable, peptide-receptive MHC I molecules have been generated using adisulfide bond between the MHC I and B2M, named "open MHC-I".[9]
The peptides are generated mainly in thecytosol by theproteasome. The proteasome is a macromolecule that consists of 28 subunits, of which half affectproteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. Proteasomes can also ligate distinct peptide fragments (termed spliced peptides), producing sequences that are noncontiguous and therefore not linearly templated in the genome. The origin of spliced peptide segments can be from the same protein (cis-splicing) or different proteins (trans-splicing).[10][11] The peptides have to be translocated from the cytosol into theendoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in thelumen of the ER. They have membrane proximalIg fold
The peptide translocation from the cytosol into the lumen of the ER is accomplished by thetransporter associated with antigen processing (TAP). TAP is a member of theABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting ofTAP1 andTAP2. The two subunits form a peptide binding site and two ATP binding sites that face the cytosol. TAP binds peptides on the cytoplasmic side and translocates them underATP consumption into the lumen of the ER. The MHC class I molecule is then, in turn, loaded with peptides in the lumen of the ER.
The peptide-loading process involves several other molecules that form a large multimeric complex called thepeptide loading complex[12] consisting of TAP,tapasin,calreticulin,calnexin, andErp57 (PDIA3). Calnexin acts to stabilize the class I MHC α chains prior to β2m binding. Following complete assembly of the MHC molecule, calnexin dissociates. The MHC molecule lacking a bound peptide is inherently unstable and requires the binding of the chaperones calreticulin and Erp57. Additionally, tapasin binds to the MHC molecule and serves to link it to the TAP proteins and facilitates the selection of peptide in an iterative process called peptide editing,[13][14][15] thus facilitating enhanced peptide loading and colocalization.
Once the peptide is loaded onto the MHC class I molecule, the complex dissociates and it leaves the ER through thesecretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves severalposttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to theN-glycan regions of the protein, followed by extensive changes to the N-glycans in thegolgi apparatus. The N-glycans mature fully before they reach the cell surface.
Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum (ER) are removed from the ER via thesec61 channel into the cytosol,[16][17] where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to a MHC class I molecule.
For example, an interaction of sec61 with bovinealbumin has been observed.[18]
MHC class I molecules are loaded with peptides generated from the degradation ofubiquitinated cytosolic proteins inproteasomes. As viruses induce cellular expression of viral proteins, some of these products are tagged for degradation, with the resulting peptide fragments entering the endoplasmic reticulum and binding to MHC I molecules. It is in this way, the MHC class I-dependent pathway of antigen presentation, that the virus infected cells signal T-cells that abnormal proteins are being produced as a result of infection.
The fate of the virus-infected cell is almost always induction ofapoptosis throughcell-mediated immunity, reducing the risk of infecting neighboring cells. As an evolutionary response to this method of immune surveillance, many viruses are able to down-regulate or otherwise prevent the presentation of MHC class I molecules on the cell surface. In contrast to cytotoxic T lymphocytes,natural killer (NK) cells are normally inactivated upon recognizing MHC I molecules on the surface of cells. Therefore, in the absence of MHC I molecules, NK cells are activated and recognize the cell as aberrant, suggesting that it may be infected by viruses attempting to evade immune destruction. Several human cancers also show down-regulation of MHC I, giving transformed cells the same survival advantage of being able to avoid normal immune surveillance designed to destroy any infected or transformed cells.[19]
The MHC class I genes originated in themost recent common ancestor of alljawed vertebrates, and have been found in all living jawed vertebrates that have been studied thus far.[2] Since their emergence in jawed vertebrates, this gene family has been subjected to many divergent evolutionary paths asspeciation events have taken place. There are, however, documented cases of trans-speciespolymorphisms in MHC class I genes, where a particularallele in an evolutionary related MHC class I gene remains in two species, likely due to strong pathogen-mediatedbalancing selection bypathogens that can infect both species.[20]Birth-and-death evolution is one of the mechanistic explanations for the size of the MHC class I gene family.
Birth-and-death evolution asserts thatgene duplication events cause the genome to contain multiple copies of a gene which can then undergo separate evolutionary processes. Sometimes these processes result inpseudogenization (death) of one copy of the gene, though sometimes this process results in two new genes with divergent function.[21] It is likely that human MHC class Ib loci (HLA-E, -F, and -G) as well as MHC class I pseudogenes arose from MHC class Ia loci (HLA-A, -B, and -C) in this birth-and-death process.[22]