Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes.
Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes.
复制标题
弗林蛋白酶前结构域促进肝细胞中磷脂转移蛋白蛋白酶体降解。
DOI：
10.1161/jaha.118.008526
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发表时间：
2018-04-21
影响因子：
5.4
通讯作者：
Jiang XC
中科院分区：
文献类型：
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作者：
Yu Y;Lei X;Jiang H;Li Z;Creemers JWM;Zhang M;Qin S;Jin W;Jiang XC
磷脂转移蛋白（PLTP）是脂蛋白代谢和动脉粥样硬化发展的主要调节因子之一；然而，人们对PLTP的调控机制知之甚少。本研究探讨了弗林蛋白酶（furin）的肝脏前结构域（前弗林蛋白酶，profurin）表达对PLTP加工和功能的影响。
我们利用在小鼠肝脏中表达profurin的腺病毒来评估PLTP活性、含量以及血浆脂质水平。我们在人肝癌细胞系中共同表达PLTP和profurin，并研究它们之间的相互作用。我们发现，与对照组相比，在所有测试的小鼠模型中，profurin的表达显著降低了血浆脂质、血浆PLTP活性及含量。此外，profurin的表达还显著降低了肝脏PLTP活性和蛋白质水平。我们进一步通过体内和体外实验方法探究其作用机制。我们发现profurin可与细胞内的PLTP相互作用，促进其泛素化和蛋白酶体降解，从而导致肝细胞分泌的PLTP减少。弗林蛋白酶并不切割PLTP；相反，它可能通过其前结构域与PLTP形成复合物。
我们的研究表明，肝脏PLTP蛋白会因profurin的表达而被靶向进行蛋白酶体降解，这可能是PLTP调控的一种新的翻译后机制。
Phospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development; however, little is known about the regulation of PLTP. The effect of hepatic prodomain of furin (profurin) expression on PLTP processing and function is investigated. We used adenovirus expressing profurin in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We coexpressed PLTP and profurin in human hepatoma cell line cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity, and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explored the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP; instead, it forms a complex with PLTP, likely through its prodomain. Our study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin expression, which could be a novel posttranslational mechanism underlying PLTP regulation.