Pathway: Antigen processing: Ubiquitination & Proteasome degradation
Reactions in pathway: Antigen processing: Ubiquitination & Proteasome degradation :
Antigen processing: Ubiquitination & Proteasome degradation
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).
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).
Adaptive immunity refers to antigen-specific immune response efficiently involved in clearing the pathogens. The adaptive immune system is comprised of B and T lymphocytes that express receptors with remarkable diversity tailored to recognize aspects of particular pathogens or antigens. During infection, dendritic cells (DC) which act as sentinels in the peripheral tissues recognize and pick up the pathogen in the form of antigenic determinants and then process these antigens and present them to T cells. These T cells of appropriate specificity respond to the antigen, and either kill the pathogen directly or secrete cytokines that will stimulate B lymphocyte response. B cells provide humoral immunity by secreting antibodies specific for the pathogen or antigen.
Humans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first critical hours and days of exposure to a new pathogen, our innate immune system.