Ubiquitin-proteasome pathway as a target for therapeutic strategies

Abstract

In Eukaryota, the majority of intracellular proteins are degraded by the ubiquitin-26S proteasome pathway. Through degradation of proteins tagged with polyubiquitin chains, the 26S proteasomes, multicatalytic proteolytic complexes, participate in regulation of key cellular processes such as cell cycle, proliferation and cell differentiation, apoptosis, transcription, signal transduction, morphogenesis, immune response, response to stress and to extracellular effectors, modulation of cell-surface receptors, antigen presentation, proteolysis of enzymes and regulatory proteins, and protein quality control in endoplasmic reticulum. Dysfunction of the ubiquitin-proteasome pathway is associated with many diseases, including cancer, neurodegeneration, autoimmune and inflammatory response, as well as infectious diseases. In recent years, besides proteasomes, the enzymes that drive ubiquitination and deubiquitination have entered clinical trials as potential therapeutic targets. Small molecular inhibitors against proteasomes have been discovered, as well as inhibitors of the ubiquitin cascade enzymes and deubiquitinating enzymes. Second generation inhibitors of proteasomes have been successfully approved for clinical application.