View source for Biology:MHC class I

{{short description|Protein of the immune system}}
{{Pfam_box
| Symbol = MHC class I
| Name = MHC class I
| image = MHC Class 1.svg
| width =
| caption = Schematic representation of MHC class I
| InterPro= 
| PROSITE = 
| SCOP = 
| TCDB =
| OPM family=
| OPM protein=
| Pfam= 
| PDB=
| Membranome superfamily= 63
}}

'''MHC class I molecules''' are one of two primary classes of [[Biology:Major histocompatibility complex|major histocompatibility complex]] (MHC) molecules (the other being [[Biology:MHC class II|MHC class II]]) and are found on the cell surface of all nucleated cells in the bodies of [[Biology:Vertebrate|vertebrate]]s.<ref>{{cite journal | vauthors = Hewitt EW | title = The MHC class I antigen presentation pathway: strategies for viral immune evasion | journal = Immunology | volume = 110 | issue = 2 | pages = 163–9 | date = October 2003 | pmid = 14511229 | pmc = 1783040 | doi = 10.1046/j.1365-2567.2003.01738.x }}</ref><ref name=":0">{{cite journal | vauthors = Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H | title = Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man | journal = Immunological Reviews | volume = 190 | pages = 95–122 | date = December 2002 | pmid = 12493009 | doi = 10.1034/j.1600-065x.2002.19008.x | s2cid = 41765680 }}</ref> They also occur on [[Biology:Platelet|platelet]]s, but not on [[Biology:Red blood cell|red blood cell]]s. Their function is to display peptide fragments of proteins from within the cell to cytotoxic 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 present [[Chemistry:Peptide|peptide]]s derived from [[Biology:Cytosol|cytosol]]ic proteins, the pathway of MHC class I presentation is often called ''cytosolic'' or ''endogenous pathway''.<ref>http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/HLA.html#Class_I_Histocompatibility_Molecules Kimball's Biology Pages, Histocompatibility Molecules</ref>

In humans, the [[Biology:Human leukocyte antigen|HLAs]] corresponding to MHC class I are [[Biology:HLA-A|HLA-A]], [[Biology:HLA-B|HLA-B]], and [[Biology:HLA-C|HLA-C]].

== Function ==
Class I MHC molecules bind [[Chemistry:Peptide|peptide]]s generated mainly from degradation of cytosolic proteins by the [[Biology:Proteasome|proteasome]]. The MHC I:peptide complex is then inserted via 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 to [[Biology:Cytotoxic T cell|cytotoxic T cell]]s (CTLs). However, class I MHC can also present peptides generated from exogenous proteins, in a process known as [[Biology:Cross-presentation|cross-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 for natural killer cells (NKs). Reduction in the normal levels of surface class I MHC, a mechanism employed by some viruses<ref>{{cite journal | vauthors = Hansen TH, Bouvier M | title = MHC class I antigen presentation: learning from viral evasion strategies | journal = Nature Reviews. Immunology | volume = 9 | issue = 7 | pages = 503–13 | date = July 2009 | pmid = 19498380 | doi = 10.1038/nri2575 | s2cid = 9278263 }}</ref> and certain tumors to evade CTL responses, activates NK cell killing.

===PirB and visual plasticity===

Paired-immunoglobulin-like receptor B (PirB), an MHCI-binding receptor, is involved in the regulation of visual [[Biology:Neuroplasticity|plasticity]].<ref name="ReferenceA">{{cite journal | vauthors = Syken J, Grandpre T, Kanold PO, Shatz CJ | title = PirB restricts ocular-dominance plasticity in visual cortex | journal = Science | volume = 313 | issue = 5794 | pages = 1795–800 | date = September 2006 | pmid = 16917027 | doi = 10.1126/science.1128232 | bibcode = 2006Sci...313.1795S | s2cid = 1860730 }}</ref> PirB is expressed in the [[Biology:Central nervous system|central nervous system]] and diminishes [[Medicine:Ocular dominance|ocular dominance]] [[Biology:Neuroplasticity|plasticity]] in the developmental [[Biology:Critical period|critical period]] and adulthood.<ref name="ReferenceA"/>  When the function of PirB was abolished in mutant mice, [[Medicine:Ocular dominance|ocular dominance]] [[Biology:Neuroplasticity|plasticity]] became more pronounced at all ages.<ref name="ReferenceA"/> PirB loss of function mutant mice also exhibited enhanced [[Biology:Neuroplasticity|plasticity]] after monocular deprivation during the [[Biology:Critical period|critical period]].<ref name="ReferenceA"/> These results suggest PirB may be involved in modulation of [[Biology:Synaptic plasticity|synaptic plasticity]] in the [[Biology:Visual cortex|visual cortex]].

== Structure ==
MHC class I molecules are heterodimers that consist of two polypeptide chains, α and [[Biology:Beta-2 microglobulin|β<sub>2</sub>-microglobulin]] (B2M). The two chains are linked noncovalently via interaction of B2M and the α<sub>3</sub> domain. Only the α chain is polymorphic and encoded by a [[Biology:Human leukocyte antigen|HLA gene]], while the B2M subunit is not polymorphic and encoded by the [[Biology:Beta-2 microglobulin|Beta-2 microglobulin]] gene. The α<sub>3</sub> domain is plasma membrane-spanning and interacts with the [[Biology:CD8|CD8]] co-receptor of [[Biology:T cell|T-cells]]. The α<sub>3</sub>-CD8 interaction holds the MHC I molecule in place while the T cell receptor (TCR) on the surface of the cytotoxic T cell binds its α<sub>1</sub>-α<sub>2</sub> heterodimer ligand, and checks the coupled peptide for antigenicity. The α<sub>1</sub> and α<sub>2</sub> 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.<ref>{{cite journal | vauthors = Burrows SR, Rossjohn J, McCluskey J | title = Have we cut ourselves too short in mapping CTL epitopes? | journal = Trends in Immunology | volume = 27 | issue = 1 | pages = 11–6 | date = January 2006 | pmid = 16297661 | doi = 10.1016/j.it.2005.11.001 }}</ref>

While a high-affinity peptide and the B2M subunit are normally required to maintain a stable [[Biology:Ternary complex|ternary complex]] between the peptide, MHC I, and B2M, under subphysiological temperatures, stable, peptide-deficient MHC I/B2M heterodimers have been observed.<ref>{{Cite journal |last1=Ljunggren |first1=Hans-Gustaf |last2=Stam |first2=Nico J. |last3=Öhlén |first3=Claes |last4=Neefjes |first4=Jacques J. |last5=Höglund |first5=Petter |last6=Heemels |first6=Marie-Thérèse |last7=Bastin |first7=Judy |last8=Schumacher |first8=Ton N. M. |last9=Townsend |first9=Alain |last10=Kärre |first10=Klas |last11=Ploegh |first11=Hidde L. |date=1990-08-02 |title=Empty MHC class I molecules come out in the cold |url=https://www.nature.com/articles/346476a0 |journal=Nature |language=en |volume=346 |issue=6283 |pages=476–480 |doi=10.1038/346476a0 |issn=0028-0836}}</ref><ref>{{Cite journal |last1=Schumacher |first1=Ton N.M. |last2=Heemels |first2=Marie-Thérèse |last3=Neefjes |first3=Jacques J. |last4=Kast |first4=W.Martin |last5=Melief |first5=Cees J.M. |last6=Ploegh |first6=Hidde L. |date=August 1990 |title=Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro |url=https://linkinghub.elsevier.com/retrieve/pii/009286749090020F |journal=Cell |language=en |volume=62 |issue=3 |pages=563–567 |doi=10.1016/0092-8674(90)90020-F}}</ref> Synthetic stable, peptide-receptive MHC I molecules have been generated using a disulfide bond between the MHC I and B2M, named "open MHC-I".<ref>{{Cite journal |last1=Sun |first1=Yi |last2=Young |first2=Michael C. |last3=Woodward |first3=Claire H. |last4=Danon |first4=Julia N. |last5=Truong |first5=Hau V. |last6=Gupta |first6=Sagar |last7=Winters |first7=Trenton J. |last8=Font-Burgada |first8=Joan |last9=Burslem |first9=George M. |last10=Sgourakis |first10=Nikolaos G. |date=2023-06-20 |title=Universal open MHC-I molecules for rapid peptide loading and enhanced complex stability across HLA allotypes |journal=Proceedings of the National Academy of Sciences |language=en |volume=120 |issue=25 |pages=e2304055120 |doi=10.1073/pnas.2304055120 |pmid=37310998 |issn=0027-8424|pmc=10288639 }}</ref>

==Synthesis==
[[Image:MHC Class I processing.svg|thumb|right|200px|Simplified diagram of cytoplasmic protein degradation by the proteasome, transport into endoplasmic reticulum by TAP complex, loading on MHC class I, and transport to the surface for presentation]]
The peptides are generated mainly in the [[Biology:Cytosol|cytosol]] by the [[Biology:Proteasome|proteasome]]. The proteasome is a macromolecule that consists of 28 subunits, of which half affect [[Biology:Proteolysis|proteolytic]] 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).<ref>{{cite journal |last1=Faridi |first1=Pouya |last2=Li |first2=Chen |last3=Ramarathinam |first3=Sri H. |last4=Vivian |first4=Julian P. |last5=Illing |first5=Patricia T. |last6=Mifsud |first6=Nicole A. |last7=Ayala |first7=Rochelle |last8=Song |first8=Jiangning |last9=Gearing |first9=Linden J. |last10=Hertzog |first10=Paul J. |last11=Ternette |first11=Nicola |last12=Rossjohn |first12=Jamie |last13=Croft |first13=Nathan P. |last14=Purcell |first14=Anthony W. |title=A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands |journal=Science Immunology |date=12 October 2018 |volume=3 |issue=28 |pages=eaar3947 |doi=10.1126/sciimmunol.aar3947|pmid=30315122 |url=http://orca.cf.ac.uk/116124/1/A%20subset%20of%20HLA-1%20peptide%20%20%20J%20ROSSJOHN%20Science%20Immunol.pdf |doi-access=free }}</ref><ref>{{cite journal |last1=Liepe |first1=Juliane |last2=Marino |first2=Fabio |last3=Sidney |first3=John |last4=Jeko |first4=Anita |last5=Bunting |first5=Daniel E. |last6=Sette |first6=Alessandro |last7=Kloetzel |first7=Peter M. |last8=Stumpf |first8=Michael P. H. |last9=Heck |first9=Albert J. R. |last10=Mishto |first10=Michele |title=A large fraction of HLA class I ligands are proteasome-generated spliced peptides |journal=Science |date=21 October 2016 |volume=354 |issue=6310 |pages=354–358 |doi=10.1126/science.aaf4384|pmid=27846572 |bibcode=2016Sci...354..354L |hdl=10044/1/42330 |s2cid=41095551 |url=http://spiral.imperial.ac.uk/bitstream/10044/1/42330/2/Liepe2016_Science.pdf |hdl-access=free }}</ref> The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in the [[Biology:Lumen (anatomy)|lumen]] of the ER. They have membrane proximal Ig fold

==Translocation and peptide loading==
The peptide translocation from the cytosol into the lumen of the ER is accomplished by the [[Biology:Transporter associated with antigen processing|transporter associated with antigen processing]] (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. 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 under [[Chemistry:Adenosine triphosphate|ATP]] 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 the [[Biology:Peptide loading complex|Peptide loading complex]]<ref>{{cite journal | vauthors = Blees A, Januliene D, Hofmann T, Koller N, Schmidt C, Trowitzsch S, Moeller A, Tampé R | title = Structure of the human MHC-I peptide-loading complex | journal = Nature | volume = 551 | issue = 7681 | pages = 525–528 | date = November 2017 | pmid = 29107940 | doi = 10.1038/nature24627 | bibcode = 2017Natur.551..525B | s2cid = 4447406 }}</ref> consisting of TAP, tapasin, [[Biology:Calreticulin|calreticulin]], [[Biology:Calnexin|calnexin]], and Erp57 ([[Biology:PDIA3|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,<ref>{{cite journal | vauthors = Howarth M, Williams A, Tolstrup AB, Elliott T | title = Tapasin enhances MHC class I peptide presentation according to peptide half-life | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 32 | pages = 11737–42 | date = August 2004 | pmid = 15286279 | pmc = 511045 | doi = 10.1073/pnas.0306294101 | bibcode = 2004PNAS..10111737H | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wearsch PA, Cresswell P | title = Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer | journal = Nature Immunology | volume = 8 | issue = 8 | pages = 873–81 | date = August 2007 | pmid = 17603487 | doi = 10.1038/ni1485 | s2cid = 29762957 }}</ref><ref>{{cite journal | vauthors = Thirdborough SM, Roddick JS, Radcliffe JN, Howarth M, Stevenson FK, Elliott T | title = Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide-MHC class I complexes | journal = European Journal of Immunology | volume = 38 | issue = 2 | pages = 364–9 | date = February 2008 | pmid = 18196518 | doi = 10.1002/eji.200737832 | s2cid = 28659293 | doi-access = free }}</ref> 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 the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan regions of the protein, followed by extensive changes to the N-glycans in the [[Biology:Golgi apparatus|Golgi apparatus]]. The N-glycans mature fully before they reach the cell surface.

==Peptide removal==
Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum (ER) are removed from the ER via the [[Biology:Sec61|sec61]] channel into the cytosol,<ref name="pmid10933400">{{cite journal | vauthors = Koopmann JO, Albring J, Hüter E, Bulbuc N, Spee P, Neefjes J, Hämmerling GJ, Momburg F | title = Export of antigenic peptides from the endoplasmic reticulum intersects with retrograde protein translocation through the Sec61p channel | journal = Immunity | volume = 13 | issue = 1 | pages = 117–27 | date = July 2000 | pmid = 10933400 | doi = 10.1016/S1074-7613(00)00013-3 | display-authors = etal | doi-access = free }}</ref><ref name="pmid14644099">{{cite journal | vauthors = Albring J, Koopmann JO, Hämmerling GJ, Momburg F | title = Retrotranslocation of MHC class I heavy chain from the endoplasmic reticulum to the cytosol is dependent on ATP supply to the ER lumen | journal = Molecular Immunology | volume = 40 | issue = 10 | pages = 733–41 | date = January 2004 | pmid = 14644099 | doi = 10.1016/j.molimm.2003.08.008 }}</ref> 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 bovine [[Biology:Albumin|albumin]] has been observed.<ref name="pmid15546887">{{cite journal | vauthors = Imai J, Hasegawa H, Maruya M, Koyasu S, Yahara I | title = Exogenous antigens are processed through the endoplasmic reticulum-associated degradation (ERAD) in cross-presentation by dendritic cells | journal = International Immunology | volume = 17 | issue = 1 | pages = 45–53 | date = January 2005 | pmid = 15546887 | doi = 10.1093/intimm/dxh184 | doi-access = free }}</ref>

==Effect of viruses==
MHC class I molecules are loaded with peptides generated from the degradation of ubiquitinated cytosolic proteins in proteasomes. 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 of [[Biology:Apoptosis|apoptosis]] through [[Biology:Cell-mediated immunity|cell-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.<ref>{{cite journal | vauthors = Wang Z, Zhang L, Qiao A, Watson K, Zhang J, Fan GH | title = Activation of CXCR4 triggers ubiquitination and down-regulation of major histocompatibility complex class I (MHC-I) on epithelioid carcinoma HeLa cells | journal = The Journal of Biological Chemistry | volume = 283 | issue = 7 | pages = 3951–9 | date = February 2008 | pmid = 18083706 | doi = 10.1074/jbc.m706848200 | doi-access =  free}}</ref>

==Genes and isotypes==
* Very polymorphic
** {{Gene|HLA-A}} ([[Biology:HLA-A|HLA-A]])
** {{Gene|HLA-B}} ([[Biology:HLA-B|HLA-B]])
** {{Gene|HLA-C}} ([[Biology:HLA-C|HLA-C]])
* Less polymorphic
** {{Gene|HLA-E}} (HLA-E)
** {{Gene|HLA-F}} (HLA-F)
** {{Gene|HLA-G}} (HLA-G)
** {{Gene|HLA-K}} (pseudogene)
** {{Gene|HLA-L}} (pseudogene)

== Evolutionary history ==
The MHC class I genes originated in the most recent common ancestor of all jawed vertebrates, and have been found in all living jawed vertebrates that have been studied thus far.<ref name=":0" /> Since their emergence in jawed vertebrates, this gene family has been subjected to many divergent evolutionary paths as [[Biology:Speciation|speciation]] events have taken place. There are, however, documented cases of trans-species polymorphisms in MHC class I genes, where a particular [[Biology:Allele|allele]] in an evolutionary related MHC class I gene remains in two species, likely due to strong pathogen-mediated [[Biology:Balancing selection|balancing selection]] by [[Biology:Pathogen|pathogen]]s that can infect both species.<ref>{{cite journal | vauthors = Azevedo L, Serrano C, Amorim A, Cooper DN | title = Trans-species polymorphism in humans and the great apes is generally maintained by balancing selection that modulates the host immune response | journal = Human Genomics | volume = 9 | pages = 21 | date = September 2015 | issue = 1 | pmid = 26337052 | pmc = 4559023 | doi = 10.1186/s40246-015-0043-1 | doi-access = free }}</ref> [[Birth–death process|Birth-and-death]] evolution is one of the mechanistic explanations for the size of the MHC class I gene family.

=== Birth-and-death of MHC class I genes ===
Birth-and-death evolution asserts that [[Biology:Gene duplication|gene duplication]] events cause the genome to contain multiple copies of a gene which can then undergo separate evolutionary processes. Sometimes these processes result in [[Biology:Pseudogene|pseudogenization]] (death) of one copy of the gene, though sometimes this process results in two new genes with divergent function.<ref>{{cite journal | vauthors = Nei M, Rooney AP | title = Concerted and birth-and-death evolution of multigene families | journal = Annual Review of Genetics | volume = 39 | issue = 1 | pages = 121–52 | date = 2005-11-14 | pmid = 16285855 | pmc = 1464479 | doi = 10.1146/annurev.genet.39.073003.112240 }}</ref> 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.<ref>{{cite journal | vauthors = Hughes AL | title = Origin and evolution of HLA class I pseudogenes | journal = Molecular Biology and Evolution | volume = 12 | issue = 2 | pages = 247–58 | date = March 1995 | pmid = 7700152 | doi = 10.1093/oxfordjournals.molbev.a040201 | doi-access = free }}</ref>

== References ==
{{reflist|30em}}

== External links ==
* {{MeshName|Histocompatibility+Antigens+Class+I}}
* {{MeshName|MHC+Class+I+Genes}}

{{T cell receptor}}

[[Category:Genes]]
[[Category:Immune system]]
[[Category:Protein targeting]]
[[Category:Single-pass transmembrane proteins]]

{{Sourceattribution|MHC class I}}