2014
DOI: 10.1128/mcb.01140-13
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The E3 Ubiquitin Ligase MARCH6 Degrades Squalene Monooxygenase and Affects 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase and the Cholesterol Synthesis Pathway

Abstract: bThe mevalonate pathway is used by cells to produce sterol and nonsterol metabolites and is subject to tight metabolic regulation. We recently reported that squalene monooxygenase (SM), an enzyme controlling a rate-limiting step in cholesterol biosynthesis, is subject to cholesterol-dependent proteasomal degradation. However, the E3-ubiquitin (E3) ligase mediating this effect was not established. Using a candidate approach, we identify the E3 ligase membrane-associated RING finger 6 (MARCH6, also known as TEB4… Show more

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Cited by 145 publications
(187 citation statements)
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“…7B). Differences in exogenous expression levels of the WT and RING-dead MARCH6 proteins were reported previously (31,50) and are known to be due to differences in MARCH6 degradation (42). Our data suggest that the CTE is required for MARCH6 self-regulation through proteasome-dependent degradation, and both residues Gly-885 and Asn-890 are important for this.…”
Section: The Doa10 Cte Promotes Efficient Deg1supporting
confidence: 53%
“…7B). Differences in exogenous expression levels of the WT and RING-dead MARCH6 proteins were reported previously (31,50) and are known to be due to differences in MARCH6 degradation (42). Our data suggest that the CTE is required for MARCH6 self-regulation through proteasome-dependent degradation, and both residues Gly-885 and Asn-890 are important for this.…”
Section: The Doa10 Cte Promotes Efficient Deg1supporting
confidence: 53%
“…7A). We previously identified MARCH6 as an E3 ligase involved in the proteasomal degradation of SM and HMGCR (28). However, in this case we excluded its role in targeting DHCR7 for degradation (Fig.…”
Section: Discussionmentioning
confidence: 94%
“…7A). Considering that the E3 ligase MARCH6 can target both SM and HMGCR for degradation, we employed two independent siRNAs to knock down MARCH6, as we have done previously (28). However, DHCR7 degradation was not rescued (Fig.…”
Section: Low Dhcr7 Expression In Slos Mutationsmentioning
confidence: 99%
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“…While HMCGR is post-translationally regulated by non-cholesterol sterols, including 24,25-dihydrolanosterol (12) and oxysterols (13), SM is directly regulated by cholesterol itself (10), which results in its degradation via the ubiquitin-proteasome system. MARCH6 has been identified as the E3 ligase responsible for this targeted degradation (14,15). Cholesterol-dependent degradation of SM can be reversed by unsaturated fatty acids, which stabilise SM by preventing its polyubiquitination by MARCH6 (16).…”
Section: Sm: a Post-translational Control Point Post-hmgcrmentioning
confidence: 99%