Class I MHC: Wikis

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Schematic representation of MHC class I

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other one being simply MHC class II) and are found on every nucleated cell of the body (and thus not on red blood cells). Their function is to display fragments of proteins from within the cell to T cells; healthy cells will be ignored while cells containing foreign proteins will be attacked by the immune system. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.[1]

Contents

Function

MHC class I molecules bind peptides mainly generated from degradation of cytosolic proteins. The MHC-I peptide complex is then inserted into the plasma membrane of the cell. The peptide is bound to the extracellular part of the MHC-I molecule. The function of the MHC-I is thus to display to the environment, specifically cytotoxic T cells (CTLs), the proteins that are being produced within the cell.

A normal cell will display peptides from normal cellular proteins on its MHC-I, and CTLs will not be activated in response to them. When a cell expresses peptides that are not normally present in cells, such as after viral infection, these foreign peptides will be recognized by CTLs, which will become activated and kill the cell. Additionally, reduction in the normal levels of expression of MHC-I, which can occur in some virally infected cells as well as some cancer cells, will also activate CTLs to destroy the cell.

Structure

MHC Class I structure.

MHC class I molecule consists of two polypeptide chains, α and β2-microglobulin. The two chains are associated noncovalently. Only the α chain is polymorphic and encoded by MHC gene, while the β2-microglobulin is not polymorphic and encoded by other gene. The α3 domain is transmembrane where CD8 binds. The α1 and α2 domains fold to make up a groove for peptides to bind. MHC class I molecule binds peptides that are 8-10 amino acid in length (Parham 87).

Production

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 mainly generated in the cytosol by the proteasome. The proteasome is a macromolecule that consists of 28 subunits, of which half affect proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. 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 lumen of the ER.

Translocation

The peptide translocation from the cytosol into the lumen of the ER is accomplished by the 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 lumen of the cytosol. TAP binds peptides on the cytoplasmic site and translocates them under 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 consisting of TAP, tapasin, calreticulin, calnexin, and ERP57.

Once the peptide is loaded onto the MHC class I molecule, 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 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 sec61 channel into the cytosol,[2][3] where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to an MHC class I molecule.

For example, an interaction of sec61 with bovine albumin has been observed.[4]

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. In this way, the MHC class I-dependent pathway of antigen presentation is the primary way for a virus-infected cell to signal T cells that abnormal proteins are being synthesized as a result of infection.

The fate of the virus-infected cell is almost always induction of apoptosis through 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 they 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. [5]

Genes and isotypes

Additional images

References

  1. ^ http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/HLA.html#Class_I_Histocompatibility_Molecules Kimball's Biology Pages, Histocompatibility Molecules
  2. ^ Koopmann JO, Albring J, Hüter E, et al. (July 2000). "Export of antigenic peptides from the endoplasmic reticulum intersects with retrograde protein translocation through the Sec61p channel". Immunity 13 (1): 117–27. PMID 10933400. http://linkinghub.elsevier.com/retrieve/pii/S1074-7613(00)00013-3.  
  3. ^ Albring J, Koopmann JO, Hämmerling GJ, Momburg F (January 2004). "Retrotranslocation of MHC class I heavy chain from the endoplasmic reticulum to the cytosol is dependent on ATP supply to the ER lumen". Mol. Immunol. 40 (10): 733–41. PMID 14644099. http://linkinghub.elsevier.com/retrieve/pii/S0161589003002530.  
  4. ^ Imai J, Hasegawa H, Maruya M, Koyasu S, Yahara I (January 2005). "Exogenous antigens are processed through the endoplasmic reticulum-associated degradation (ERAD) in cross-presentation by dendritic cells". Int. Immunol. 17 (1): 45–53. doi:10.1093/intimm/dxh184. PMID 15546887. http://intimm.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15546887.  
  5. ^ Wang, Ziqing et al. 2008. Activation of CXCR4 Triggers Ubiquitination and Down-regulation of Major Histocompatibility Complex Class I (MHC-I) on Epithelioid Carcinoma HeLa Cells. Journal of Biological Chemistry 283: 3951-3959.

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