The Cholesterol Synthesis Enzyme Lanosterol 14α‐Demethylase is Post‐Translationally Regulated by the E3 Ubiquitin Ligase MARCH6

Abstract

Cholesterol synthesis is a complex process with over twenty enzymes involved. Each enzyme within the pathway undergoes distinct regulation to maintain cholesterol homeostasis. Typically, enzymes within the pathway are degraded in response to a high sterol status, but some are highly stable. In this study, we demonstrate that an enzyme at the branch point in the pathway, lanosterol 14α‐demethylase (LDM), undergoes unique regulation. We show that the preceding enzyme, lanosterol synthase (LSS) is stable, whilst LDM is rapidly degraded. Surprisingly, this degradation is not triggered by sterols but by nitric oxide. Here we identify that the important E3 ubiquitin ligase, MARCH6, is responsible for facilitating the ubiquitination and proteasomal degradation of LDM and also the terminal cholesterol synthesis enzyme, 24‐dehydrocholesterol reductase (DHCR24). Our work highlights MARCH6 as the first example of an E3 ubiquitin ligase which targets multiple steps in a single biochemical pathway and indicates new facets in the control of cholesterol synthesis.Support or Funding InformationThis work was supported by the Australian Research Council Grant DP170101178. The PhD students were funded by the Research Training Program from the Australian Government Department of Education.