Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting

Abstract

Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve, it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely nonlysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanismbased drugs.

Lysosomal killing ofMycobacteriummediated by ubiquitin-derived peptides is enhanced by autophagy

“…Ubiquitin is best characterized as a posttranslational addition to proteins that targets them for degradation through the proteosome (14). In addition to this ''classic'' route for protein breakdown, it is also known that ubiquitin regulates trafficking of proteins in the endocytic pathway.…”

Homozygosity mapping with SNP arrays identifiesTRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11)

“…This system of protein degradation is a multistep cascade that relies on a series of enzymes to tag substrates with multiubiquitin for degradation (47)(48)(49)(50). The third enzyme in this series, an E3 ubiquitin-protein ligase, of which there are many in the human genome, is involved in the recognition and transfer of ubiquitin to the protein substrate.…”

Discovery of the ubiquitin proteasome system and its involvement in apoptosis

“…It is an honour and privilege to write a short introductory editorial to lectures [1][2][3] and interviews [4][5][6] with Aaron Ciechanover, Avram Hershko and Irwin Rose, the 2004 Nobel Laureates in Chemistry, for their pioneering work on the discovery of ubiquitin-mediated protein degradation. This is an additional tribute to these scientists, in recognition of their discovery and characterisation of the ubiquitin proteasome system (UPS), made in a small laboratory by great scientists with limited material, but not intellectual, resources.…”