New insights into the post-translational regulation of ABC lipid transporters

Aleidi SM1, Yang A1, Alrosan A1, Sharpe L2, Brown AJ2 and Gelissen IC1

  1. School of Pharmacy, Faculty of Medicine and Health, University of Sydney.
  2. School of Biotechnology and Biomolecular Sciences, University of NSW, Sydney.

A number of ABC transporters, including ABCA1, ABCG1 and its close relative ABCG4, are essential regulators of cellular lipid homeostasis. ABCA1 and ABCG1 have been studied in the context of macrophage lipid homeostasis and atherosclerosis, insulin secretion in β-cells as well as brain lipid homeostasis, with substrates including cholesterol and phospholipids. ABCG4 on the other hand is thought to transport cholesterol, oxysterols and cholesterol synthesis intermediates exclusively in the brain, and has been linked to Alzheimer’s disease due to its potential to transport amyloid-β peptides from cells. These transporters are thought to be highly regulated at the post-translational level. Our group and collaborators have previously identified two separate avenues by which these transporters can be regulated i.e. via cellular cholesterol status as well as protein ubiquitination. The rate limiting step in protein ubiquitination is carried out by E3-ubiquitin ligases that have become of interest as potential therapeutic targets in a number of disease settings. We have identified a number of E3-ligases that are involved in the regulation of ABCA1, ABCG1 and ABCG4 (Aleidi et al 2015 and 2018). Here we describe under which circumstances these ligases regulate ABC lipid transporter protein levels and activity, and propose how these pathways may be exploited in the disease context in future.