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首页> 外文期刊>Molecular and Cellular Biology >The E3 Ubiquitin Ligase MARCH6 Degrades Squalene Monooxygenase and Affects 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase and the Cholesterol Synthesis Pathway
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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

机译：E3泛素连接酶MARCH6降解角鲨烯单加氧酶并影响3-羟基-3-甲基-谷氨酰辅酶A还原酶和胆固醇的合成途径。

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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.
机译：甲羟戊酸途径被细胞用于产生固醇和非固醇代谢产物，并受到严格的代谢调节。我们最近报道，角鲨烯单加氧酶（SM），一种控制胆固醇生物合成中限速步骤的酶，受胆固醇依赖的蛋白酶体降解。但是，没有建立介导这种作用的E3-泛素（E3）连接酶。使用候选方法，我们将E3连接酶膜相关的RING指6（MARCH6，也称为TEB4）识别为控制SM降解的连接酶。我们发现，MARCH6和SM在物理上相互作用，并且与充当E3连接酶的MARCH6一致，其过表达以RING依赖的方式降低了SM的丰度。相反，MARCH6的敲低会增加SM蛋白的水平，并防止其胆固醇调节的降解。另外，这增加了细胞相关的SM活性，但出乎意料地伴随着SM上游的通量增加。由该观察结果提示，我们发现敲除MARCH6还可控制肝细胞和模型细胞系中3-羟基-3-甲基-戊二酰辅酶A还原酶（HMGCR）的水平。总之，MARCH6控制SM和HMGCR的丰度，使其成为通过胆固醇合成途径的主要流量调节剂。

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