Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY.
Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Taishan Medical University, Taian, China.
J Am Heart Assoc. 2018 Apr 21;7(9):e008526. doi: 10.1161/JAHA.118.008526.
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.
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剂之一；然而，对于 PLTP 的调节知之甚少。本研究旨在探讨肝蛋白原酶（profurin）表达对 PLTP 加工和功能的影响。
我们使用腺病毒在小鼠肝脏中表达 profurin，以评估 PLTP 活性、质量和血浆脂质水平。我们在人肝癌细胞系中共同表达 PLTP 和 profurin，并研究它们的相互作用。结果发现，与对照组相比，profurin 的表达显著降低了所有测试小鼠模型中的血浆脂质、血浆 PLTP 活性和质量。此外，profurin 的表达显著降低了肝 PLTP 活性和蛋白水平。我们进一步通过体内和体外方法探讨了其机制。我们发现 profurin 可以与细胞内的 PLTP 相互作用，促进其泛素化和蛋白酶体降解，从而减少肝细胞中 PLTP 的分泌。furin 不会切割 PLTP；相反，它与 PLTP 形成复合物，可能通过其前导序列。
本研究揭示了肝 PLTP 蛋白通过 profurin 的表达被靶向进行蛋白酶体降解，这可能是 PLTP 调节的一种新的翻译后机制。
