Ubiquitin-Proteasome Pathway in the Pathogenesis of Liver Disease

Abstract

32 32.1 Introduction The discovery of the ubiquitin-proteasome pathway as a regulated system of protein digestion within all cells [32] has led to an appreciation of the impor-tance of protein turnover control. This control is a mechanism for regulation of cellular processes and quality control of intracellular proteins. Many liver cell functions are regulated by this mechanism of protein degradation. These include cell cycle check points and activation of transcription factors such as nuclear factor-κB (NF-κB) (Chapter 29), and hy-poxia inducible factor-1α (HIF-1α) (Chapter 26) [28, 67, 71]. The loss of proteasomes or the inhibi-tion of the ubiquitin-proteasome pathway can lead to hepatocellular injury including proliferation and apoptosis [74, 107], and hepatic inclusions of ag-gregated cytokeratins [24]. Liver cell gene expres-sions, dependent on transcription factor activation by the proteasome, could impede the inflammatory response of the liver and the response to hypoxic in-jury. The importance of the ubiquitin-proteasome pathway to the homeostatic mechanisms involved in liver injury is the focus of this review. 32.2 Ubiquitin-Proteasome Pathway The enzymes that catalyze ubiquitin activation, conjugation and ligation are depicted as E1, E2, and E3, respectively in Fig. 32.1. Ubiquitin is indicated as a shaded circle. Note that the polyubiquitinated protein indicated by Cn+1 docks at the 19S protea-some. Alpha (α) units of the 20S proteasome par-ticle are shown in gray, while the beta (β) subunits are shown in white. Both types of subunits make up the 20S catalytic core of the proteasome. The arrows shown at the 19S proteasome indicate that the ubiq-uitinated protein is deubiquitinated by proteasomal deubiquitinase before the protein unfolds and enters the chamber of the proteasome to undergo digestion. Ubiquitin (shown as Ub) exists as a pool of free mol-ecules (upper left of Fig. 32.1), which can be attached either singly or in polyubiquitin chains to the sub-strate protein (bottom center). The polyubiquitinat-ed protein substrate is then degraded by the 26S pro-teasome to smaller peptides, which can then either be degraded to amino acids by other proteinases or be presented on the surface of the cell membrane in the immune cells. The beta subunits in the middle of the 20S proteasome include chymotrypsin-like and trypsin-like catalytic enzymes, which digest the proteins that enter the chamber. The entrance of the proteins into the digestion chamber is gated by alpha subunits. In this way the digestion of proteins is selectively regulated. Proteins that are digested by the 26S proteasomes must first be targeted to pro-teasomes by at least a 4 polyubiquitin chain where the C-terminal glycine is covalently bound to lysine residues in the protein destined to be digested by the proteasome.