Proteases/Proteasome

Proteases, also known as peptidases or proteinases, belong to the subgroup of enzymes referred to as hydrolases. Proteases catalyze the cleavage of peptide bonds within proteins and split proteins into smaller peptide fragments. They are now considered to be extremely important signaling molecules because of their involvement in many vital cell processes, including blood coagulation, digestion of dietary proteins, immune function, maturation of prohormones, bone formation, programmed cell death and the recycling of oxidized and damaged cellular proteins. Physiologically, protease signaling pathways are precisely modulated in order to maintain biological homeostasis.^[1] When dysregulation of protease activity occurs, pathologies, including cardiovascular and inflammatory diseases, cancer, osteoporosis and neurological disorders.
A finely tuned equilibrium exists between protein synthesis and protein degradation to ensure cellular homeostasis. Protein degradation is predominantly catalyzed by the proteasome, a very large (2.5MDa) multi-catalytic multi-subunit protein complex. Proteasomes are non-lysosomal proteolytic complexes localized primarily in the cytoplasm and in the nucleus of eukaryotic cells. The 26S proteasome is a multi-catalytic enzyme with a highly ordered structure composed of at least 32 different subunits, arranged in two sub-complexes (a 20S core protease and a 19S regulatory particle). The composition of inner ring β-subunits in the proteasome can be modified to form the immunoproteasome, by incorporating inducible forms by de novo synthesis, thus replacing their constitutive counterparts. For example, induction of proteasome subunits by γ-interferon induces LMP2, MECL-1, and LMP7 subunits, which replace constitutive catalytic subunits β1, β2, and β5. LMP2, MECL-1, and LMP7 subunits have altered catalytic properties compared with constitutive subunits. γ-interferon-induced subunits enhance proteasomal generation of MHC I-binding peptides. PA28 (a.k.a. 11S regulatory particle) does not contain any ATPases and can promote the degradation of short peptides but not of complete proteins. Thus, the immunoproteasome plays a critical role in the function of the adaptive immune system. Proteins are degraded to 8-10-mer peptides by the immunoproteasome and then imported into the endoplasmic reticulum by the peptide transporter associated with antigen processing (TAP). MHC class I receptors containing bound peptides are then presented on the cell surface. Targeting the proteasome system may be a useful strategy to generate anti-tumor effects.^[2] Proteasome inhibitors induce apoptosis of cells following an initial accumulation of short-lived proteins such as p53, p27, pro-apoptotic Bcl-2 family members.^[3] Although mechanisms of release remain unknown, there is proven scientific and clinical interest and value in measuring plasma/serum proteasome levels. Highly selective inhibitors of proteasome activity (including MG-132, MLN9708, Carfilzomib) have been applied to the clinical treatment of multiple myeloma and other blood cancers. ^[4]

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