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One E3 ligase targets two key control points in cholesterol synthesis (605.5)
Author(s) -
Brown Andrew,
Sharpe Laura,
Loregger Anke,
Cook Emma,
Phan Lisa,
Stevenson Julian,
Zelcer Noam
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.605.5
Subject(s) - ubiquitin ligase , sterol , cholesterol , squalene monooxygenase , dna ligase , chemistry , biochemistry , regulator , ubiquitin , microbiology and biotechnology , sterol regulatory element binding protein , gene knockdown , enzyme , biosynthesis , biology , gene
The mevalonate pathway is used by cells to produce sterol and non‐sterol 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 ligase (E3) mediating this effect was not established. Using a candidate approach, we identify the E3 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, its over‐expression 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 elevated levels of squalene, SM’s substrate. Prompted by this observation, we found that MARCH6 also controls the level of endogenous and ectopically expressed HMGCR in hepatocytes and model cell‐lines. 25‐hydroxycholesterol induces rapid degradation of HMGCR in the presence of MARCH6, and absence of the ligase blunted sterol regulation. In conclusion, degradation of both HMGCR and SM by MARCH6 establishes it as a major regulator of flux through the cholesterol synthesis pathway .