Document Detail


The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway.
MedLine Citation:
PMID:  24449766     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The 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) as the ligase controlling degradation of SM. We find that MARCH6 and SM physically interact, and consistent with MARCH6 acting as an E3 ligase, its overexpression reduces SM abundance in a RING-dependent manner. Reciprocally, knockdown of MARCH6 increases the level of SM protein and prevents its cholesterol-regulated degradation. Additionally, this increases cell-associated SM activity but is unexpectedly accompanied by increased flux upstream of SM. Prompted by this observation, we found that knockdown of MARCH6 also controls the level of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) in hepatocytes and model cell lines. In conclusion, MARCH6 controls abundance of both SM and HMGCR, establishing it as a major regulator of flux through the cholesterol synthesis pathway.
Authors:
Noam Zelcer; Laura J Sharpe; Anke Loregger; Ika Kristiana; Emma C L Cook; Lisa Phan; Julian Stevenson; Andrew J Brown
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2014-01-21
Journal Detail:
Title:  Molecular and cellular biology     Volume:  34     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2014 Apr 
Date Detail:
Created Date:  2014-03-10     Completed Date:  2014-05-14     Revised Date:  2014-10-07    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1262-70     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cell Line
Cholesterol / biosynthesis*
Enzyme Stability
Gene Knockdown Techniques
HEK293 Cells
Hep G2 Cells
Hepatocytes / metabolism
Humans
Hydroxymethylglutaryl CoA Reductases / metabolism*
Membrane Proteins / antagonists & inhibitors,  genetics,  metabolism*
Mevalonic Acid / metabolism
Models, Biological
Recombinant Proteins / genetics,  metabolism
Signal Transduction
Squalene Monooxygenase / genetics,  metabolism*
Ubiquitin-Protein Ligases / antagonists & inhibitors,  genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Membrane Proteins; 0/Recombinant Proteins; 97C5T2UQ7J/Cholesterol; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases; EC 1.14.13.132/Squalene Monooxygenase; EC 6.3.2.19/MARCH6 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases; S5UOB36OCZ/Mevalonic Acid
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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