The E3 Ubiquitin Ligase MARCH6 Degrades Squalene Monooxygenase and Affects 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase and the Cholesterol Synthesis Pathway

MARCH6 is involved in degradation of squalene epoxidase.

“The ER-resident ubiquitin E3 ligase MARCH6 was shown to be involved in the degradation of squalene epoxidase (Zelcer et al., 2014).”

MARCHF6 is an ERAD-associated E3 ubiquitin ligase that post-transcriptionally regulates squalene epoxidase (SQLE).

“We and others have recently identified the ERAD-associated E3 ubiquitin ligase MARCHF6 as a post-transcriptional regulator of squalene epoxidase (SQLE), the enzyme in cholesterol biosynthesis that commits the mevalonate pathway to sterol production [22,23].”

SQLE and PLIN2 were more abundant in Marchf6LKO and Marchf6(-/-) livers.

“In addition, SQLE and PLIN2, two established MARCHF6 targets and proxies for its activity [22,31], were more abundant in those mice (Figure 5D and Supplementary Fig. 5C).”

A prominent feature of MARCHF6 loss in hepatocytes is increased abundance of SQLE protein and heightened sterol pathway throughput.

“As such, a prominent feature of MARCHF6 loss in hepatocytes is increased abundance of SQLE protein and heightened sterol pathway throughput, as was also observed in a non-hepatic cell system [22].”

SQLE and PLIN2 are established MARCHF6 targets and proxies for its activity.

“In addition, SQLE and PLIN2, two established MARCHF6 targets and proxies for its activity [22,31], were more abundant in those mice (Figure 5D and Supplementary Fig. 5C).”

MARCH6 controls stability of SQLE, a rate-limiting enzyme in cholesterol synthesis, in a cholesterol-dependent manner.

“We have recently reported that MARCH6, an ERAD-associated E3 (36), controls stability of SQLE, a rate-limiting enzyme in cholesterol synthesis, in a cholesterol-dependent manner (16).”

Loss of MARCH6 activity enhances production of nonsaponifiable lipids by the mevalonate pathway.

“As a result, loss of MARCH6 activity enhances production of nonsaponifiable lipids by the mevalonate pathway.”

Loss of MARCH6 increases metabolic flux through the mevalonate pathway due to dysregulated control of the pathway at the level of the rate-limiting enzyme SQLE.

“We have previously reported that loss of MARCH6 increases metabolic flux through the mevalonate pathway due to dysregulated control of the pathway at the level of the rate-limiting enzyme SQLE (16).”

A major outcome of MARCH6 loss is an increase in basal levels of HMGCR protein.

“This is in line with our earlier observation indicating that a major outcome of MARCH6 loss is an increase in basal levels of HMGCR protein.”

Silencing MARCH6 elevates basal levels of HMGCR.

“we also found that the silencing of MARCH6 regulates the basal levels of HMGCR, comparable to what was shown for the E3 HRD1 (16,19).”

MARCH6 can also regulate the level of HMGCR, positioning it as an important regulator of flux through the mevalonate pathway.

“In our previous study, we reported that in addition to controlling the levels of SQLE, MARCH6 could also regulate the level of HMGCR, thereby positioning it as an important regulator of flux through the mevalonate pathway (16).”

MARCH6-dependent regulation of HMGCR is at least in part posttranscriptional, as HMGCR protein expressed from a constitutive promoter is also subject to MARCH6-dependent regulation.

“This regulation was at least in part posttranscriptional as HMGCR protein expressed from a constitutive promoter was also subject to MARCH6-dependent regulation.”