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NOBEL LAUREATE PAPERS

Intracellular Protein Degradation: From a Vague Idea Thru the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting^*

Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel

To whom requests for reprints should be addressed at ¹ Faculty of Medicine, Technion-Israel Institute of Technology, Efron Street, Bat Galim, P.O. Box 9649, Haifa 31096 Israel. E-mail: c_tzachy{at}netvision.net.il

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 non-lysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitinproteasome 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 mechanism-based drugs.

Key Words: ubiquitin • proteasome • protein degradation • lysosome

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