Insights into the regulatory mechanisms of xenophagy as revealed by chemical genetics

Abstract

Cells maintain homeostasis by a continuous process of synthesis and degradation of their constituent proteins and organelles. This facilitates the cell to remain as a dynamic entity responding rapidly to changing extracellular environment. The landmark discovery of lysosomes in 1955 by Prof. Christian de Duve led to the identification of pathways by which the cell degrades proteins and organelles (De Duve et al., 1955; De Duve and Wattiaux, 1966). The two major intracellular degradation systems include the Ubiquitin-Proteasome System (UPS) and macroautophagy. UPS is a two-step process for degrading short-lived and soluble proteins in eukaryotes. It involves tagging of a substrate protein with multiple ubiquitin molecules through covalent attachment and subsequent degradation of the tagged protein by 26S proteasome. It is a tunnelshaped protein complex made up of a 20S core particle and two 19S cap protein subunits. The process involves the action of three enzymes to conjugate ubiquitin to the lysine residues of the substrate- E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme) and E3 (ubiquitin ligase). The ubiquitinated proteins are recognized by 19S cap protein and the proteolysis occurs in 20S core subunit (Myung et al., 2001).