Review The ubiquitin-proteasome system DIPANKAR NANDI*, PANKAJ TAHILIANI, ANUJITH KUMAR and DILIP CHANDU Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India *Corresponding author (Fax, 91-80-23600814; Email,
[email protected]) The 2004 Nobel Prize in chemistry for the discovery of protein ubiquitination has led to the recognition of cellular proteolysis as a central area of research in biology. Eukaryotic proteins targeted for degradation by this pathway are first ‘tagged’ by multimers of a protein known as ubiquitin and are later proteolyzed by a giant enzyme known as the proteasome. This article recounts the key observations that led to the discovery of ubiquitin-proteasome system (UPS). In addition, different aspects of proteasome biology are highlighted. Finally, some key roles of the UPS in different areas of biology and the use of inhibitors of this pathway as possible drug targets are discussed. [Nandi D, Tahiliani P, Kumar A and Chandu D 2006 The ubiquitin-proteasome system; J. Biosci. 31 137–155] 1. Introduction biological processes, e.g. transcription, cell cycle, antigen processing, cellular defense, signalling etc. is now well In an incisive article, J Goldstein, the 1985 Nobel laureate established (Ciechanover and Iwai 2004; Varshavsky 2005). for the regulation of cholesterol metabolism (together with During the early days in the field of cytosolic protein M Brown) and Chair for the Jury for the Lasker awards, degradation, cell biologists were intrigued by the requirement laments the fact that it is hard to pick out truly original dis- of ATP in this process as it is well known that peptide bond coveries among the plethora of scientific publications hydrolysis does not require metabolic energy.