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J. Biol. Chem., Vol. 280, Issue 44, 36551-36559, November 4, 2005

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Proprotein Covertases Are Responsible for Proteolysis and Inactivation of Endothelial Lipase^*

Weijun Jin1, Ilia V. Fuki2, Nabil G. Seidah3, Suzanne Benjannet, Jane M. Glick¶, and Daniel J. Rader4

From the Department of Medicine and Center for Experimental Therapeutics and the ^¶Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennyslvania 19104-6160 and the Laboratories of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W IR7, Canada

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.

Received for publication, February 28, 2005 , and in revised form, August 2, 2005.

Addendum—During the time of preparation of this manuscript, Gauster et al. (51) reported that EL is cleaved by proprotein convertases.

^* This work was supported in part by a Scientist Development Grant from the American Heart Association (to W. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental experimental procedures and Fig. S1.

² Supported by Scientist Development Grants from the American Heart Association.

³ Supported by Canadian Institutes of Health Research Grants MGP-44363 and MGC-64518.

⁴ Supported by National Institutes of Health Grant HL55323 and a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

¹ To whom correspondence should be addressed: BRB II/III, Rm. 646, 421 Curie Blvd., Philadelphia, PA 19104-6160. Tel.: 215-573-7666; Fax: 215-573-8606; E-mail: weijun{at}mail.med.upenn.edu.

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