Cellular proteolytic systems in P450 degradation: evolutionary conservation from Saccharomycescerevisiae to mammalian liver

Abstract

Mammalian hepatic cytochromes P450 (P450s) are endoplasmic reticulum (ER)-anchored haemoproteins with the bulk of their catalytic domains exposed to the cytosol and engaged in the metabolism of numerous xeno- and endobiotics. The native P450s exhibit widely ranging half-lifes and predominantly turn over via either autophagic-lysosomal degradation (ALD) or ubiquitin-dependent 26S proteasomal degradation (UPD). The basis for this heterogeneity and differential proteolytic targeting is unknown. On the other hand, structurally/functionally inactivated P450s are predominantly degraded via UPD in a process known as ER-associated degradation (ERAD). ALD/UPD/ERAD pathways are evolutionarily highly conserved. The availability of Saccharomyces cerevisiae mutants with specific genetic defects/deletions in various ALD/UPD/ERAD-associated proteins and corresponding isogenic wild-type strains has enabled the molecular dissection of the degradation pathways for heterologously expressed mammalian P450s, leading to the identification of specific protein participants. These findings collectively attest to a highly versatile cellular system for the physiological disposal of native, senescent and/or inactivated, structurally damaged mammalian liver P450s.

Keywords::

• ALD
• ERAD
• hepatic P450
• hepatocyte
• Saccharomyces cerevisiae
• UPD

Acknowledgements

The authors gratefully thank all the members of the Correia laboratory that over the years enthusiastically contributed their talents, time, effort and skills to advancing our understanding of P450 degradation. We are also particularly grateful to R Hampton (UCSD), M Hochstrasser (Yale University) and A Cooper (University of Kansas, Missouri), for their generous gifts of yeast strains. This work would not have been possible without the financial support of NIH grants GM44037 and DK26506.