Cell Metabolism：调节胆固醇代谢的新机制

生物谷

生物谷综合：来自中国科学院上海生命科学研究院生物化学与细胞生物学研究所分子生物学重点实验室（State Key Laboratory of Molecular Biology），美国德州大学西南医学中心的研究人员鉴定出一个新的gp78结合蛋白Ufd1，并发现：Ufd1蛋白与gp78蛋白结合，增强了gp78的泛素连接酶活性，加速胆固醇合成代谢的关键酶――羟甲基戊二酰辅酶A还原酶（HMGCR）的降解，进而增强细胞对低密度脂蛋白的吸收，可降低血液胆固醇水平。

文章的通讯作者是上海生科院的宋保亮研究员，李伯良研究院，参予研究的还有曹剑和王江等人，该项目得到了国家自然科学基金委和中国科学院的资助。

胆固醇是细胞膜的重要组成成分，是合成胆汁酸和多种甾醇类激素的前体，具有重要的生理功能。但高水平胆固醇可引起多种严重的疾病，如：心脑血管疾病、老年痴呆症、胆结石等等。大量证据表明，人体血液中低密度脂蛋白的含量与动脉粥样硬化症发生密切相关，后者直接诱发冠心病和中风。通过药物手段降低血液中的低密度脂蛋白水平可显著减少患动脉粥样硬化症的风险。

HMGCR是胆固醇合成中的限速酶，目前广泛使用的降胆固醇的他汀类药物，就是HMGCR酶活性的竞争性抑制剂。但是，他汀的服用会导致HMGCR蛋白代偿性显著增多，使病人不得不服用更高剂量的他汀，造成一系列毒副作用。而宋保亮研究员领导的研究小组鉴定出Ufd1是一个新的gp78结合蛋白，gp78是介导HMGCR蛋白降解的泛素连接酶。Ufd1通过结合gp78，调节gp78的酶活性，加速HMGCR降解，减少细胞内胆固醇的合成，同时增加细胞对低密度脂蛋白的吸收，可降低血液胆固醇水平。这一重要发现不仅揭示了Ufd1参与胆固醇合成调控的新机制，而且为寻找更加有效的新型降胆固醇药物提供了靶点和研究基础。

原始出处：

Cell Metabolism, Vol 6, 115-128, 08 August 2007

Ufd1 Is a Cofactor of gp78 and Plays a Key Role in Cholesterol Metabolism by Regulating the Stability of HMG-CoA Reductase

Jian Cao,1 Jiang Wang,1 Wei Qi,1 Hong-Hua Miao,1 Jing Wang,1 Liang Ge,1 Russell A. DeBose-Boyd,2 Jing-Jie Tang,1 Bo-Liang Li,1, and Bao-Liang Song1,

1 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China
2 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA

Corresponding author
Bo-Liang Li
blli@sibs.ac.cn

Corresponding author
Bao-Liang Song
blsong@sibs.ac.cn

The membrane-anchored ubiquitin ligase gp78 promotes degradation of misfolded endoplasmic reticulum (ER) proteins and sterol-regulated degradation of HMG-CoA reductase. It was known previously that Ufd1 plays a critical role in ER-associated degradation (ERAD) together with Npl4 and VCP. The VCP-Ufd1-Npl4 complex recognizes polyubiquitin chains and transfers the ubiquitinated proteins to the proteasome. Here we show that Ufd1 directly interacts with gp78 and functions as a cofactor. Ufd1 enhances the E3 activity of gp78, accelerates the ubiquitination and degradation of reductase, and eventually promotes receptor-mediated uptake of low-density lipoprotein. Furthermore, we demonstrate that the monoubiquitin-binding site in Ufd1 is required for the enhancement of gp78 activity and that the polyubiquitin-binding site in Ufd1 is critical for a postubiquitination step in ERAD. In summary, our study identifies Ufd1 as a cofactor of gp78, reveals an unappreciated function of Ufd1 in the ubiquitination reaction during ERAD, and illustrates that Ufd1 plays a critical role in cholesterol metabolism.