Endothelial lipase is inactivated upon cleavage by the members of the proprotein convertase family

Gauster, Martin; Hrzenjak, Andelko; Schick, Katja; Frank, Saša

doi:10.1194/jlr.m400500-jlr200

Cited by 33 publications

(35 citation statements)

References 42 publications

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“…et al, the EL phospholipase activity assay described in the present paper was cited in an abstract 27) . gene polymorphisms or protein modification, affect the enzymatic activity of EL [15][16][17][18][19] . For instance, a naturally occurring variant in the EL gene (LIPG), G26S, has been reported to be associated with an elevated HDL level and exhibits impaired synthesis 15) .…”

Section: Notementioning

confidence: 99%

“…It has been reported that EL forms a head-to-tail dimer in human plasma and that homodimer formation is critical for maintenance of the EL activity 16) , as is the case with LPL and HL. In addition, EL is proteolytically processed into 40-and 28-kD fragments and inactivated by proprotein convertases 18,19) . Furthermore, human heat-inactivated serum inhibits the EL phospholipase activity 20) , indicating the existence of endogenous EL inhibitors in human serum.…”

Section: Notementioning

confidence: 99%

“…However, previous studies have also reported that the EL activity is regulated by a variety of factors [15][16][17][18][19] . Moreover, it has been postulated that endogenous EL inhibitor(s) exist in human plasma 20,21) .…”

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Plasma Activity of Endothelial Lipase Impacts High-Density Lipoprotein Metabolism and Coronary Risk Factors in Humans

Sun

Ishida

Miyashita

et al. 2014

JAT

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Aim: Endothelial lipase (EL) is a determinant of plasma levels of high-density lipoprotein cholesterol (HDL-C).However, little is known about the impact of EL activity on plasma lipid profile. We aimed to establish a new method to evaluate EL-specific phospholipase activity in humans. Methods: Plasma samples were obtained from 115 patients with coronary artery disease (CAD) and 154 patients without CAD. Plasma EL protein was immunoprecipitated using an anti-EL monoclonal antibody after plasma non-specific immunoglobulins were removed by incubation with ProteinA. The phospholipase activity of the immunoprecipitated samples was measured using a fluorogenic phospholipase substrate, Bis-BODIPY FL C11-PC. Results: The EL-specific phospholipase assay revealed that plasma EL activity was inversely correlated with HDL-C levels (R= −0.3088, p＜0.0001). In addition, the EL activity was associated with cigarette smoking. Furthermore, EL activity in CAD patients was significantly higher than that in non-CAD patients. Concomitantly, the HDL-C level in CAD patients were significantly lower than that in non-CAD patients. Conclusion: We have established a method for human plasma EL-specific phospholipase activity by combination of EL immunoprecipitation and a fluorogenic phospholipid substrate. Plasma EL activity was associated with not only plasma HDL-C levels but also the risks for CAD. J Atheroscler Thromb, 2014; 21:313-321.

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Section: Notementioning

confidence: 99%

Section: Notementioning

confidence: 99%

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Plasma Activity of Endothelial Lipase Impacts High-Density Lipoprotein Metabolism and Coronary Risk Factors in Humans

Sun

Ishida

Miyashita

et al. 2014

JAT

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“…Interestingly, there are increasing data on the proprotein convertase cleavage of HSPG ligands, indicating a possible enrichment of convertases in the vicinity of the cellular glycocalyx (19,26). It was recently found that endothelial lipase has decreased affinity for HSPG following furin cleavage (12). Similarly, in our model for PV, following cleavage and a conformational change in the capsid, the capsid would detach from HSPG and associate with a putative second receptor.…”

mentioning

confidence: 97%

Heparan Sulfate-Independent Cell Binding and Infection with Furin-Precleaved Papillomavirus Capsids

Day

Lowy

Schiller

2008

J Virol

131

140

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Papillomavirus infection normally involves virion binding to cell surface heparan sulfate proteoglycans (HSPGs). However, we found that human papillomavirus type 16 pseudovirions efficiently bound and infected cells lacking HSPGs if their L2 capsid protein was precleaved by furin, a cellular protease required for infection. The inability of pseudovirions to efficiently bind and infect cultured primary keratinocytes was also overcome by furin precleavage, suggesting that the defect involves altered HSPG modification. We conclude that the primary function of HSPG binding is to enable cell surface furin cleavage of L2 and that binding to a distinct cell surface receptor(s) is a subsequent step of papillomavirus infection.Virion attachment to cell surface receptor(s) and penetration into the cell are two obligatory early steps in viral infection. Although the identity of the receptors and the mechanism of internalization are known for many viruses, the interplay between these two steps is less well understood. We have been interested in examining the cell surface events that lead to productive entry for papillomaviruses (PV), a family of nonenveloped DNA viruses that includes the oncogenic human PV (HPV) types, such as HPV16, that are the causative agents of human cervical cancer (3). The PV capsid is composed of the following two structural proteins: the major capsid protein, L1, which can self-assemble into icosahedral viruslike particles, and the minor capsid protein, L2, whose functions are necessary for establishment of infection (4,8,16).Cell surface heparan sulfate proteoglycans (HSPGs) have been shown to be the key attachment factor for most HPV types in vitro. For example, exogenous heparin can prevent infection, and the HSPG-null cell line, pgsa-745, is inefficiently infected (13,15). Due to a deficiency in xylosyl transferase, these cells lack all proteoglycans (18).L2 proteins of all sequenced PVs contain at their N termini a consensus cleavage motif for furin, a proprotein convertase, and furin cleavage is necessary for infection (23). However, mature virions in solution are resistant to furin cleavage. Cleavage is facilitated by cell surface binding and results in a conformational change in the viral capsid on the cell surface that can be monitored by the exposure of an L2 neutralization epitope (9). Therefore, we wondered if the initial interaction of the capsid with HSPG functions primarily to facilitate furin cleavage on the cell surface and, following this, a secondary receptor is engaged, or whether HSPG binding has additional roles in the infectious process. To examine this question, here we have compared infection efficiency of the following three types of HPV16 L1/L2 green fluorescent protein-expressing pseudovirus preparations: standard pseudovirus, standard pseudovirus in the presence of exogenous furin, and furin-precleaved (FPC) pseudovirus.To produce FPC pseudovirus, we took advantage of the slow maturation of in vitro-produced pseudovirus and added furin to the pseudovirus extract prior t...

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“…The phospholipase EL that requires binding to HSPGs to degrade the circulating high density lipoprotein (42), has been recently shown to be well cleaved, and hence inactivated, in cell lines by furin, PC5A, and PACE4 (19,43), and such processing requires the presence of the CRD of PC5A (17). By Western blotting of Myc-tagged EL, we now show that full-length EL (F) is not processed into its inactive ϳ32-kDa form in either CHO-FD11 or Y1 cells (Fig.…”

Section: A-c)mentioning

confidence: 99%

The Regulated Cell Surface Zymogen Activation of the Proprotein Convertase PC5A Directs the Processing of Its Secretory Substrates

Mayer

Hamelin

Asselin

et al. 2008

Journal of Biological Chemistry

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The proprotein convertases are synthesized as zymogens that acquire activity upon autocatalytic removal of their NH 2 -terminal prosegment. Based on the convertase furin, to fold properly and gain activity, the convertases PC5A, PACE4, and PC7 are presumed to undergo two sequential prosegment cleavages in the endoplasmic reticulum and then in the trans-Golgi network. However, biochemical and immunocytochemical experiments revealed that mouse PC5A is complexed to its prosegment at the plasma membrane. This labeling is lost upon treatment with heparin and is increased by overexpressing members of the syndecan family and CD44, suggesting attachment of secreted PC5A-prosegment complex to heparan sulfate proteoglycans. Following stimulation of Y1 cells with adrenocorticotropic hormone or 8-bromo-cyclic AMP, the cell surface labeling of the prosegment of PC5A is greatly diminished, whereas the signal for mature PC5A is increased. Moreover, after stimulation, the protease activity of PC5A is enhanced, as evidenced by the cleavage of the PC5A substrates Lefty, ADAMTS-4, endothelial lipase, and PCSK9. Our data suggest a novel mechanism for PC5A activation and substrate cleavage at the cell surface, through a regulated removal of its prosegment. A similar mechanism may also apply to the convertase PACE4, thereby extending our knowledge of the molecular details of the zymogen activation and functions of these heparan sulfate proteoglycan-bound convertases.

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Endothelial lipase is inactivated upon cleavage by the members of the proprotein convertase family

Cited by 33 publications

References 42 publications

Plasma Activity of Endothelial Lipase Impacts High-Density Lipoprotein Metabolism and Coronary Risk Factors in Humans

Plasma Activity of Endothelial Lipase Impacts High-Density Lipoprotein Metabolism and Coronary Risk Factors in Humans

Heparan Sulfate-Independent Cell Binding and Infection with Furin-Precleaved Papillomavirus Capsids

The Regulated Cell Surface Zymogen Activation of the Proprotein Convertase PC5A Directs the Processing of Its Secretory Substrates

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