Prodomain of furin promotes phospholipid transfer protein proteasomal degradation in hepatocytes

Yang Yu, Xia Lei, Hui Jiang, Zhiqiang Li, John W.M. Creemers, Ming Zhang, Shucun Qin, Weijun Jin, Xian Cheng Jiang

Research output: Contribution to journalArticle

Abstract

Background--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. Methods and Results--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. Conclusions--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.

Original languageEnglish (US)
Article numbere008526
JournalJournal of the American Heart Association
Volume7
Issue number9
DOIs
StatePublished - May 1 2018

Keywords

  • Atherosclerosis
  • Furin (PCSK3)
  • Lipids and lipoprotein metabolism
  • Phospholipid transfer protein
  • Profurin
  • Proteasome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Yu, Y., Lei, X., Jiang, H., Li, Z., Creemers, J. W. M., Zhang, M., Qin, S., Jin, W., & Jiang, X. C. (2018). Prodomain of furin promotes phospholipid transfer protein proteasomal degradation in hepatocytes. Journal of the American Heart Association, 7(9), [e008526]. https://doi.org/10.1161/JAHA.118.008526