The E3 ubiquitin ligase MARCH6 is boosted by cholesterol

Sharpe LJ, Howe V and Brown AJ

UNSW Sydney NSW 2052.

The E3 ligase membrane-associated RING finger (C3HC4) 6 (MARCH6) helps control protein levels of the two rate-limiting enzymes in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and squalene monooxygenase (SM). However, little is known about how MARCH6 itself is regulated. Considering MARCH6’s role in controlling cholesterol synthesis, we hypothesised that cholesterol may regulate MARCH6. Indeed, we found that cholesterol stabilises MARCH6 protein. Preliminary evidence suggests that Insigs also play a role in regulating MARCH6’s stability. Our ongoing investigations focus on the nature of the MARCH6-Insig interplay,and whether other intermediary proteins are involved. This work provides new insights into the complex feedback mechanisms underlying cholesterol homeostasis.