生物谷綜合：來自中國科學院上海生命科學研究院生物化學與細胞生物學研究所分子生物學重點實驗室（State Key Laboratory of Molecular Biology）,，美國德州大學西南醫(yī)學中心的研究人員鑒定出一個新的gp78結(jié)合蛋白Ufd1，并發(fā)現(xiàn)：Ufd1蛋白與gp78蛋白結(jié)合,，增強了gp78的泛素連接酶活性,，加速膽固醇合成代謝的關(guān)鍵酶――羥甲基戊二酰輔酶A還原酶（HMGCR）的降解，進而增強細胞對低密度脂蛋白的吸收,，可降低血液膽固醇水平,。
文章的通訊作者是上海生科院的宋保亮研究員，李伯良研究院,，參予研究的還有曹劍和王江等人,，該項目得到了國家自然科學基金委和中國科學院的資助。
膽固醇是細胞膜的重要組成成分,，是合成膽汁酸和多種甾醇類激素的前體,，具有重要的生理功能。但高水平膽固醇可引起多種嚴重的疾病,，如：心腦血管疾病,、老年癡呆癥、膽結(jié)石等等,。大量證據(jù)表明,，人體血液中低密度脂蛋白的含量與動脈粥樣硬化癥發(fā)生密切相關(guān),，后者直接誘發(fā)冠心病和中風。通過藥物手段降低血液中的低密度脂蛋白水平可顯著減少患動脈粥樣硬化癥的風險,。
HMGCR是膽固醇合成中的限速酶,，目前廣泛使用的降膽固醇的他汀類藥物，就是HMGCR酶活性的競爭性抑制劑,。但是,，他汀的服用會導致HMGCR蛋白代償性顯著增多，使病人不得不服用更高劑量的他汀,，造成一系列毒副作用,。而宋保亮研究員領(lǐng)導的研究小組鑒定出Ufd1是一個新的gp78結(jié)合蛋白，gp78是介導HMGCR蛋白降解的泛素連接酶,。Ufd1通過結(jié)合gp78,，調(diào)節(jié)gp78的酶活性，加速HMGCR降解,，減少細胞內(nèi)膽固醇的合成,，同時增加細胞對低密度脂蛋白的吸收，可降低血液膽固醇水平,。這一重要發(fā)現(xiàn)不僅揭示了Ufd1參與膽固醇合成調(diào)控的新機制,，而且為尋找更加有效的新型降膽固醇藥物提供了靶點和研究基礎(chǔ)。
原始出處：
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
[email protected]
Corresponding author
Bao-Liang Song
[email protected]
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.
