Antigen processing: Ubiquitination & Proteasome degradation

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Homo sapiens
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Intracellular foreign or aberrant host proteins are cleaved into peptide fragments of a precise size, such that they can be loaded on to class I MHC molecules and presented externally to cytotoxic T cells. The ubiquitin-26S proteasome system plays a central role in the generation of these class I MHC antigens.
Ubiquitination is the mechanism of adding ubiquitin to lysine residues on substrate protein leading to the formation of a polyubiquitinated substrate. This process involves three classes of enzyme, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. Polyubiquitination through lysine-48 (K48) generally targets the substrate protein for proteasomal destruction. The protease responsible for the degradation of K48-polyubiquitinated proteins is the 26S proteasome. This proteasome is a two subunit protein complex composed of the 20S (catalytic core) and 19S (regulatory) proteasome complexes. The proteasome eliminates most of the foreign and non-functional proteins from the cell by degrading them into short peptides; only a small fraction of the peptides generated are of the correct length to be presented by the MHC class I system. It has been calculated that between 994 and 3122 protein molecules have to be degraded for the formation of a single, stable MHC class I complex at the cell surface, with an average effciency of 1 in 2000 (Kloetzel et al. 2004, Princiotta et al. 2003).
Literature References
PubMed ID Title Journal Year
11917093 The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction

Glickman, MH, Ciechanover, A

Physiol Rev 2002
17145306 Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions

Ploegh, HL, Loureiro, J

Adv Immunol 2006
20351195 Characterizing the specificity and cooperation of aminopeptidases in the cytosol and endoplasmic reticulum during MHC class I antigen presentation

Rock, KL, Hearn, A, York, IA, Bishop, C

J Immunol 2010
12648452 Quantitating protein synthesis, degradation, and endogenous antigen processing

Buttgereit, F, Bennink, JR, Qian, SB, Yewdell, JW, Finzi, D, Schuchmann, S, Gibbs, J, Princiotta, MF

Immunity 2003
19489725 RING domain E3 ubiquitin ligases

Deshaies, RJ, Joazeiro, CA

Annu Rev Biochem 2009
14734113 Proteasome and peptidase function in MHC-class-I-mediated antigen presentation

Ossendorp, F, Kloetzel, PM

Curr Opin Immunol 2004
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