Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of as well as experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.

The Candida albicans AAA ATPase homologue of Saccharomyces cerevisiae Rix7p (YLL034c) is essential for proper morphology, biofilm formation and activity of secreted aspartyl proteinases

Proper morphology is essential for the ability of Candida albicans to switch between yeast and hyphae and thereby sustain its virulence. Here we identified, by differential screening, a novel C. albicans AAA ATPase encoding gene, CaYLL34 (RIX7), with enhanced expression in hyphae. Phylogenetic analysis suggests that CaYLL34 belongs to a [quot ]VCP-like[quot ] subgroup of AAA ATPases essential for yeast viability and contains a bipartite nuclear localization signal. Inactivation of one copy of CaYLL34, by the URA-Blaster method, generated the heterozygous mutant strain M61. This strain has severe phenotypic alterations, such as a highly increased vacuole, abnormal cell shape and reduced growth in different conditions. Also, major pathogenicity factors are affected in M61, for instance, a significant decrease of hypha formation (>90%), surface biofilm adhesion (86%) and secreted aspartyl proteinase activity (76.5%). Our results show that the partial impairment of CaYll34p cellular levels is sufficient to affect the proper cellular morphology and pathogenicity factors and suggest that this protein is required for biogenesis of ribosomal subunits. Accordingly, we propose that the product of CaYLL34 could be tested as a novel target for antifungal drugs.