Proprotein convertases [corrected] are responsible for proteolysis and inactivation of endothelial lipase.
Plasma lipoprotein metabolism is tightly regulated by several members of the triglyceride lipase family, including endothelial lipase (EL) and lipoprotein lipase (LPL). Our previous work suggested that EL is proteolytically processed. In this report, we have used a combination of epitope tagging, mutagenesis, and N-terminal sequencing to determine the precise location of the cleavage site within EL. The cleavage occurs immediately after the sequence RNKR, a known recognition sequence for the proprotein convertase (PC) family. We demonstrate that some PCs, but not all, can proteolytically cleave EL at this site and thereby directly regulate EL enzymatic activity through modulating EL cleavage. Furthermore, specific knockdown of individual PCs proves that PCs are the proteases that cleave EL in human endothelial cells. Interestingly, a homologous site in LPL is also cleaved by PCs. This action is unusual for PCs, which are traditionally known as activators of pro-proteins, and highlights a potential role of PCs in lipid metabolism through their proteolytic processing of lipases.
Jin
Weijun
W
Department of Medicine and Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennyslvania 19104, USA. weijun@mail.med.upenn.edu
Fuki
Ilia V
IV
Seidah
Nabil G
NG
Benjannet
Suzanne
S
Glick
Jane M
JM
Rader
Daniel J
DJ
D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D008049:Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000378:metabolism; D043484:Proprotein Convertases / Q000378:metabolism*
D000939:Epitopes; D010446:Peptide Fragments; C410382:LIPG protein, human; D008049:Lipase; D008071:Lipoprotein Lipase; D043484:Proprotein Convertases