Degradation of Cell Proteins and the Generation of MHC Class I-Presented Peptides

Abstract

Major histocompatibility complex (MHC) class I molecules display on the cell surface 8- to 10-residue peptides derived from the spectrum of proteins expressed in the cells. By screening for non-self MHC-bound peptides, the immune system identifies and then can eliminate cells that are producing viral or mutant proteins. These antigenic peptides are generated as side products in the continual turnover of intracellular proteins, which occurs primarily by the ubiquitin-proteasome pathway. Most of the oligopeptides generated by the proteasome are further degraded by distinct endopeptidases and aminopeptidases into amino acids, which are used for new protein synthesis or energy production. However, a fraction of these peptides escape complete destruction and after transport into the endoplasmic reticulum are bound by MHC class I molecules and delivered to the cell surface. Herein we review recent discoveries about the proteolytic systems that degrade cell proteins, how the ubiquitin-proteasome pathway generates the peptides presented on MHC-class I molecules, and how this process is stimulated by immune modifiers to enhance antigen presentation.

Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

“…8 The TAP complex appears to preferentially bind and transport peptides that are better suited for the MHC class I binding grove, that is, peptides that are 8-10 amino acids in length, with basic or hydrophobic C-termini. 38,39 With the majority of the proteins degraded by the proteasome being self-proteins, the generation of altered forms of antigen by the immunoproteasome and the preferential transport of MHC class I-compatible antigens by TAP are extremely important in influencing the expression of foreign peptide over self-peptide. Thus, it is possible that changes in function and/or expression patterns of TAP or LMP proteins could influence the peptide repertoire expressed to circulating lymphocytes, and allow for the induction of inappropriate immune events to cryptic epitopes of self-peptides for which the immune system has not been made tolerant.…”

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

“…Immunoproteasomes contain an IFN-g inducible regulatory unit called the proteasome activator PA28 (Rock and Goldberg 1999;Kloetzel 2001). PA28 on its own can influence antigen presentation drastically, mainly by changing the kinetics of the degradation process without altering the specificity (Preckel et al 1999;Stohwasser et al 2000;Van Hall et al 2000;Kloetzel 2001;Sijts et al 2002;Sun et al 2002).…”

“…After protein substrates have been degraded, the resulting peptide fragments are translocated from the cytoplasm to the endoplasmic reticulum and then loaded onto major histocompatibility complex (MHC) class I molecules (Rock and Goldberg 1999). The recognition of the peptide-MHC complex on the cell surface by a cytotoxic T cell (CTL) causes lysis of the cell.…”

Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

“…Generally, proteins are degraded to peptides by the proteasome, loaded onto MHC class I molecules, and presented as a complex to cytotoxic T lymphocytes (CTLs) at the cell surface (Rock and Goldberg, 1999). Based on the discovery of an intimate connection between antigen presentation and protein synthesis Yewdell and colleagues postulated the defective ribosomal product (DRiP) hypothesis (Yewdell et al, 1996).…”