Abstract
The family of the secretory proprotein convertases (PCs) comprises seven basic amino acid (aa)-specific subtilisin-like serine proteinases known as PC1/3, PC2, furin, PC4, PC5/6, PACE4 and PC7, and two other PCs, SKI-1 (subtilisin-kexin isozyme-1)/S1P (site-1 protease) and PCSK9 (proprotein convertase subtilisin kexin 9) that cleave at nonbasic residues. Except for the testicular PC4, all the other convertases are expressed in brain and peripheral organs and play a critical role in various functions including the production of diverse neuropeptides as well as growth factors and receptors, the regulation of cellular adhesion/migration, cholesterol and fatty acid homeostasis, and growth/differentiation of progenitor cells. Some of these convertases process proteins that are implicated in pathologies, including cancer malignancies, tissue regeneration, and viral infections. The implication of some of these convertases in sterol/lipid metabolism has only recently been appreciated. SKI-1/S1P activates the synthesis of cholesterol and fatty acids as well as the LDL receptor (LDLR), whereas PCSK9 inactivates the LDLR. Moreover, furin, PC5 and/or, PACE4 inactivates endothelial and lipoprotein lipases. Humans and mice exhibiting either a gain or loss of function of PCSK9 through specific point mutations or knockouts develop hypercholesterolemia and hypocholesterolemia phenotypes, respectively. A PCSK9 inhibitor in combination with statins offers a most promising therapeutic target to treat cardiovascular disorders including dyslipidemias. Specific inhibitors/modulators of the other PCs should find novel therapeutic applications in the control of PC-regulated pathologies.
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Introduction
Atherosclerosis and its major sequelae, coronary artery disease (CAD), are the leading causes of mortality and morbidity in developed countries. Incidence of fatal and non-fatal acute myocardial infarctions is expected to increase dramatically in the next two decades. Cardiovascular risk factors include dyslipidemia, hypertension, diabetes, smoking, obesity, age, psychological stress, and male gender. The most potent factor, dyslipidemia, often reflects a high ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C). The data from the Cholesterol Treatment Trialists (CTT) Consortium [6] reveal that for each 1 mmol/l reduction in LDL-C induced by statins yields ∼20% more protection against vascular disease, implying that the lower we drive the ratio of plasma LDL-C/HDL-C, the greater is the benefit to patients at risk to develop cardiovascular complications. Current guidelines recommend a target level of LDL-C <1.8 mmol/l (<70 mg/dl) in high-risk individuals and in the secondary prevention of CAD [67]. Among the effective LDL-C-lowering drugs are statins [14], inhibitors of the rate-limiting hydroxylmethylglutaryl coenzyme A reductase (HMG-CoA) needed for cholesterol synthesis. Although well tolerated statins are limited in their capacity to lower LDL-C. New approaches include NPC1L1 intestinal sterol transporter blocker ezetimibe that reduces LDL-C by an additional 20% [111]. Clearly, novel strategies to further decrease levels of circulating LDL-C in combination therapy are needed [17, 107].
Cardiovascular regulation is dependent on a myriad of factors, including protease activities [107]. The mammalian genome database predicts the presence of 550–700 protease genes (∼2% of genes), covering all potential enzymatic cleavages of a given species at all developmental stages [7, 73]. The most abundant serine proteases represent about one third of all five protease classes [73]. However, proteases do not operate alone but form cascades, regulatory circuits, and networks that all dynamically interconnect to form the protease web [69]. All known vasoactive proteins and peptides result from proteolytic processing and activation events. The proprotein convertases (PCs) are implicated in the limited proteolysis of secretory precursor proteins resulting in a diversity of bioactive proteins and peptides, and in some cases, in inactivation of key proteins [88]. Mammalian PCs are the central focus of this manuscript. They are encoded by genes numbered from PCSK1 to PCSK9 (PC subtilisin/kexin). The nine known PCs (Fig. 1) are as follows: PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9 [85, 86, 90]. The first seven are basic amino acid (aa)-specific PCs cleaving precursor proteins at single or paired basic residues. These PCs are phylogenetically more closely related to each other and to yeast kexin than to SKI-1/S1P or PCSK9, which belong to the pyrolysin [89] and proteinase K [85] subfamilies, respectively. All PCs contain a signal peptide, a prosegment, and a catalytic domain. Just following the catalytic domain, the basic aa-specific convertases exhibit a β-barrel P-domain that apparently stabilizes the catalytic pocket. The C-terminal domain of each convertase contains unique sequences regulating their cellular localization and trafficking. PC5 and PACE4 contain a specific Cys-rich domain (CRD), which, in combination with TIMPs, binds to HSPG at the cell surface. In contrast, PCSK9 exhibits a Cys-His-rich domain (CHRD) that is required for cell surface binding in an LDLR-dependent fashion [85, 89]. Some of these PCs play critical roles in regulating lipids and/or sterols [88]. PCSK9 enhances the degradation of the LDL receptor (LDLR) [10, 55, 56, 70], SKI-1/S1P activates specific membrane-bound transcription factors, e.g., SREBP-1 and -2 [20], PC5A, PACE4, and/or furin cleave/inactivate EL and LPL, which are critical in HDL, VLDL, and chylomicron metabolism (Fig. 2) [37]. Familial autosomal dominant hypercholesterolemia (ADH) is characterized by high levels of plasma cholesterol, xanthomas, and premature CAD. In vivo functions of PCSK9 have been shown in humans exhibiting gain- or loss-of-function mutations associated with hypercholesterolemia [1, 2, 4, 11, 50, 63, 110] or hypocholesterolemia [12, 21, 44, 117] and in mouse knockout (KO) models [76]. This led to classifying PCSK9 as the third gene associated with familial ADH (incidence ∼2.3%) with LDLR (incidence ∼67%) and APOB (apolipoprotein B; incidence ∼14%) as the other two (Fig. 3) [1]. Although LDLR and PCSK9 genes are coregulated, PCSK9 triggers the degradation of LDLR [5, 27]. PCSK9 inhibition is thus a promising complement to statin therapy [5, 17, 117]. In vivo functions of PCSK9 have been reported in mouse KO models [76] and in natural gain- or loss-of-function human variants [1, 10, 21, 50, 110].
The role of PCs in cardiovascular functions and disease
Background on lipid homeostasis
Lipoproteins shuttle hydrophobic molecules (cholesteryl esters and triglycerides) between organs in the aqueous environment of plasma. They are macromolecules with a single envelope of phospholipids and free (unesterified) cholesterol and a core of triglycerides and cholesteryl esters [33]. The major lipoprotein classes are the triglyceride-rich chylomicrons and VLDL, LDL, and HDL lipoproteins. The protein component of LDL is apoB, whereas VLDL also contains apoE and apoCs. The denser HDL contains apoAs, Cs, D, and E [39]. The LDL particles are atherogenic, that is, they cause atherosclerosis [19]. LDLs are cleared from blood by LDLR-mediated endocytosis. SK1-1/S1P and PCSK9 are involved in transcriptional regulation and cellular processing of the LDLR, respectively. HDL-C levels are inversely related to the risk of CAD. HDL particles are formed predominantly in the liver and intestine and are extensively modified in the plasma by EL and hepatic lipase (HL) and lipid transfer proteins. Presently, few therapeutic options raise HDL-C to prevent heart disease [51].
This paper explores the possible role of some of the convertases implicated in HDL metabolism and exclusively concentrates on the lipidemic effects of the PCs and will not detail the other numerous implications of the PCs in cancer, metastasis, atherosclerosis, restenosis, and viral infections and other pathologies. For these, the reader is referred to excellent reviews [9, 40, 83, 90, 97, 108].
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PCSK9 (originally named NARC-1): PCSK9 was first characterized by our group in 2003; it is highly expressed in the liver, gut, and kidney [85]. PCSK9 mRNA levels are upregulated by SREBP-2 and downregulated by cholesterol [27, 35, 57]. We established the first association between single-point mutations in PCSK9 and ADH in two French families [1] (Fig. 4). Later on, Cohen et al. [21] showed that two nonsense PCSK9 mutations resulting in a loss of function are associated with hypocholesterolemia in 1.8% of black subjects [44] (Fig. 4). Only one of these two mutations was also found in European–Americans at a lower frequency (0.12%). PCSK9 mutations associated with hypercholesterolemia result in a gain of function via an enhanced PCSK9 activity that triggers the degradation of LDLR [55] in acidic compartments, likely endosomes/lysosomes [5, 10, 56]. By a yet unknown mechanism, high levels of PCSK9 lead to a faster rate of degradation of the cell surface LDLR, resulting in increased circulating LDL-C, as the LDL uptake in hepatocytes by the Ldlr is diminished. In agreement, Pcsk9 −/− mice exhibit an increased LDLR protein, but not mRNA, and a twofold drop in circulating cholesterol [76]; whereas mice overexpressing PCSK9 after recombinant adenoviral infections exhibit high levels of circulating cholesterol [10, 46, 55, 70]. Two healthy and fertile females, 32 [117] and 21 [34] years old, with either homozygote C679X or heterozygote ΔR97 and Y142X variations, respectively, were reported (Fig. 4). Although the Y142X truncation leads to the complete loss of PCSK9 expression, the deletion of ΔR97 and the C679X variant results in either an unprocessed zymogen or an autocatalytically processed PCSK9 that remains in the endoplasmic reticulum (ER) [117]. Their LDL-C is remarkably low, ∼15 mg/dl. This, and the observation that loss-of-function nonsense mutations could lead to 88% reduction in CAD over a 15-year-period, indicate that the inhibition of PCSK9 or decreasing its levels may represent a safe and effective strategy for the control of hyperlipidemia [44].
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Interplay between PCSK9, LDLR, and apoB—In vivo studies in hypercholesterolemic patients [68] and in a stable transfectant in rat liver cells [104] showed that hypercholesterolemic mutants of PCSK9 resulted in the increased release of apoB-containing lipoproteins. In vivo evidence that PCSK9 enhances apoB release, even in the absence of LDLR, came from its adenovirus-mediated overexpression in Ldlr −/− mice that led to the increased VLDL- and LDL-associated cholesterol [10]. However, adenovirus infection at lower titers revealed no significant effects on apoB secretion [70]. Twenty-four hour-fasted mice overexpressing adenovirus PCSK9 showed massive hyperlipidemia as a consequence of increased secretion of apoB100-containing VLDLs [22, 47]. Primary hepatocytes from Pcsk9 −/− mice showed some reduction in secretion of apoB as compared to Pcsk9 +/+ hepatocytes [76]. That LDLR may attenuate hepatic apoB secretion was first observed by Twisk et al. [113] who showed that, by an unknown mechanism, Ldlr −/− hepatocytes secreted apoB100 at a 3.5-fold higher rate than did Ldlr +/+ hepatocytes. The mechanisms of PCSK9-mediated degradation of LDLR or apoB and their interplay along the secretory pathway need clarification. As hepatic overproduction of apoB100 is one of the causes for a subset of familial-combined hyperlipidemia, to better understand the impact of PCSK9 on the synthesis and secretion of apoB-containing lipoproteins is essential.
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PCSK9 degradation versus gain-/loss-of-function mutations—To date, almost 35 aa variations have been reported (see Fig. 4; [1, 2, 12, 21, 32, 44, 50, 72, 91, 110, 117]). Until the crystal structure of PCSK9 is solved, the biochemical analysis of the corresponding variants is crucial to better understand its biology. As gain-of-function mutations are rather rare in proteases, we suspected that the level of active enzyme was modulatory and thereby able to modulate in return LDLR levels (Fig. 5). We discovered that two French mutations associated with hypercholesterolemia, F216L and R218S [1, 2], modify a typical RXXR218 site for basic aa-specific PCs (Fig. 6), best cleaved by furin and PC5 [11, 86]. Although not in the vicinity of this PC site, the Anglo-Saxon D374Y mutation also confers resistance to cleavage. The extent of this cleavage was highly enhanced when we optimized the site for PC cleavage into an RRRR218EL, resulting in a loss of function of PCSK9, i.e., the inability to trigger LDLR degradation (Fig. 6) [11]. In contrast, the A443T substitution [44] associated with hypocholesterolemia leads to an increase sensitivity to PC-mediated cleavage [11]. Thus, the half-life of PCSK9 seems to directly modulate the circulating LDL-C. Whether cellular and/or circulating PCSK9 is subjected to degradation by other enzymes, such as cell surface metalloproteinases or plasma proteases, is yet to be defined.
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Cellular trafficking of PCSK9 and colocalization with its dominant partner LDLR—Like most PCs, PCSK9 is autocatalytically processed in the ER, before its exit from this compartment. Although most PCs are activated after a secondary cleavage of their prosegment before their secretion (Fig. 7), PCSK9 is rapidly secreted as a tight complex with its N-terminal prosegment [10, 85]. As the prosegments of PCs are usually potent inhibitors, this suggests that the secreted PCSK9 is inactive. The secreted form of PCSK9 was shown to be internalized into endosomes via cell-surface binding in an LDLR-dependent manner [18]. In agreement, media swaps [18] or addition of purified PCSK9 to naive cells [45] resulted in the degradation of the LDLR. Very recently, it was demonstrated that PCSK9 and LDLR could interact directly at the cell surface [45], but whether this is cell-type dependant and requires another accessory protein is yet to be determined. We also recently completed an extensive immunocytochemical study of the cellular localization of PCSK9 and its mutants in primary hepatocytes and cell lines [64]. Our data show that wild type and hypercholesterolemic variants of PCSK9 co-localize with LDLR in early and late endosomes, whereas variants associated with hypocholesterolemia do not [64].
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SKI-1: In contrast to basic aa-specific PCs, SKI-1 (also known as S1P) cleaves substrates in the general motif RX(V,L)(K,F,L)↓ (the downward arrow emphasizes that cleavage occurs C-terminal to K, F, or L) [71, 89]. ProSKI-1 is autocatalytically cleaved into a mature ∼106 kDa membrane-bound form [89] and a secreted ∼98 kDa shed form [29]. Its PCSK8 gene, ubiquitously expressed [89], is located on human chromosome 16 and mouse chromosome 8 [105]. In the absence of sterols, SKI-1 cleaves the membrane-bound transcription factors sterol regulatory element-binding proteins (SREBPs) in their luminal loop [81], leading to the release of a cytosolic basic helix-loop-helix transcription factor. In the nucleus, this activates the transcription of LDLR and all the genes involved in cholesterol and fatty acid synthesis [81]. In the presence of sterols, SREBP cleavage is inhibited, and hence, transcription of its target genes is reduced, although the reverse is true in the absence of sterols [81]. Other transmembrane transcription factors cleaved by SKI-1 include the ER-stress response factor ATF6 and CREB-like transcription factors Luman and CREB4 [16, 49, 53, 61, 71, 81, 103, 114, 115]. Recently, we developed in vitro fluorogenic assays of SKI-1 activity as well as cellular inhibitors of this convertase that block viral infectivity through the inhibition of viral surface glycoprotein processing [8, 71, 74, 112].
SKI-1 KO—Lethality occurs at the blastocyst stage in Pcsk8 −/− mice with the absence of inner cell mass formation [59]. A conditional KO of Pcsk8 in the liver, using the Mx1-cre transgene, led to a partial disruption to the gene (85%) and caused a 50% reduction in rates of cholesterol and fatty acid synthesis, plus very low levels of nuclear SREBPs and reduced mRNA of their target genes [114]. SKI-1 may be involved in cartilage formation as disorganization of chondrocytes was observed in zebrafish deficient in SKI-1 [84].
PC5: PC5 (also called PC6 [62]) was first identified and cloned by our group [54, 58]. Human PCSK5 encodes two alternatively spliced isoforms PC5A (915 aa) and PC5B (1870 aa) [54]. Both zymogens undergo a first autocatalytic cleavage in the ER and a second in the trans-Golgi network (TGN) [24, 65] or possibly at the cell surface (Mayer and Seidah, in preparation). Although devoid of a transmembrane domain, PC5A can exert its proteolytic action at the cell surface, as it is retained at the plasma membrane as a complex with tissue inhibitors of metalloproteases (TIMPs) and heparan sulfate proteoglycans [66].
Using in situ hybridization and/or quantitative reverse transcription polymerase chain reaction, we documented tissue distribution patterns of PC5 during development, adulthood, and in various cell lines [30]. By embryonic day E15.5, the PC5 pattern of expression becomes similar to the adult: strong labeling in adrenal cortex, small intestine, kidney, and vasculature [30]. PC5A is the predominant isoform in adult mouse tissues except in the intestine and kidney where PC5B predominates [30].
Many substrates are reported to be efficiently processed ex vivo by PC5: matrix metalloproteases and ADAM family enzymes [95, 102]; growth factors such PDGF-A [94], PDGF-B [93], and VEGF-C [92]; and receptors such as IGF-1R [41], integrins [13, 52], renin [58, 77], and lipases [37]. We showed that in atherosclerotic plaques and during arterial restenosis, expression of PC5 is highly upregulated [96, 98–102]. High expression of PC5 in enterocytes suggests a possible role in processing protein substrates that could regulate food and/or sterol/lipid absorption [54, 87]. It was recently reported that a locus on chromosome 9, close to PCSK5, is implicated in lipid regulation in humans [31]. PC5 is thus a good candidate proteinase in the control of both arterial restenosis [97] and the levels of circulating HDL.
PC5 KO—To investigate physiological roles of PC5, we generated a Pcsk5-deficient allele missing exon 4 that encodes the catalytic Asp173. Although heterozygote Δ4/+ mice are healthy and fertile, homozygote Δ4/Δ4 embryos die at E4.5-E7.5 [30].
Furin: Furin, an ubiquitous membrane protein [78], is initially produced as a ∼104 kDa precursor rapidly converted into an active ∼98 kDa form [23, 48, 87]. This autocatalytic cleavage, occurring in the ER (Fig. 6), is a prerequisite for the exit of mature furin molecules out of the ER to the TGN and cell surface [60, 106]. Deduced from many studies is that furin and PC5 exhibit partial redundancy of their in vitro selectivity and sensitivity to certain modified serpin inhibitors [36, 86, 109]. Candidate substrates described for furin in vitro include many vasoactive peptides and proteins involved in cardiovascular tissue remodeling [3, 108]. Most of these cleavages occur in the TGN, at cell surface, or in endosomes but rarely in the ER [82]. It is noted that furin, PACE4, and PC5 can inactivate endothelial and lipoprotein lipases [37]. Moreover, furin plays a key role in blood pressure regulation though the activation of transforming growth factor β (TGFβ) [26], a process that was recently shown to be inhibited by the binding of Emilin-1 to proTGFβ [75, 116]. Very recently, it was shown that angiopoietin-like proteins Angptl-3 and Angptl-4 were processed at an internal RRKR site to release these lipoprotein lipase inhibitors in circulation [42, 43]. This suggests that a furin-like enzyme is the responsible convertase of LPL, a hypothesis that will need further confirmation. With tissue-specific conditional KOs, we may soon be able to establish if such ex vivo observations also pan out in vivo.
Furin KO—Furin is detected at E7.5 in the endoderm and mesoderm. During the late somite stages, it is seen in the cardiovascular system [80, 118]. Inactivation of the fur gene (Pcsk3) causes embryonic death ≈E11 because of hemodynamic insufficiency and cardiac ventral closure defects [80]. Mutant embryos failed to develop large vessels despite the presence of endothelial cell precursors. TGFβ1 was recently shown to be efficiently processed by furin [26], and the inactivation of its gene produces a phenotype similar to that of furin-null embryos [25, 28].
A conditional KO in liver, with the deletion of exon 2 dependent on the Cre expression from the Mx1-cre transgene, resulted in viable Pcsk3 flox/flox Tg(Mx1-cre) mice with almost no phenotype. This demonstrated the existence of some redundancy with other convertases, as some typical furin substrates were still cleaved, although to a lesser extent [79].
The need for better treatments of dyslipidemias
It is becoming very clear that lowering the levels of circulating LDL-C and/increasing that of HDL-C over a lifetime has profound effects on the incidence of cardiovascular disorders and dyslipidemias. This includes myocardial infarcts, hypertension, and endothelial dysfunction leading to atherosclerosis, as well as stroke. Indeed, recent clinical trials indicated that treatment of these disorders should be based on global cardiovascular risks rather than only on the levels of circulating cholesterol. It is now recognized that the major risk factors in cardiovascular disorders are as follows: abnormal lipid contents, smoking, diabetes, high blood pressure, abdominal obesity, unhealthy diet, and lack of physical activity. Although improved diet and increased physical activity can be achieved by modifications of lifestyle, the other parameters are usually regulated with specific medication, e.g., the use of statins, ezetimibe, thiazide, β-blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers.
The available data suggest that some of the basic aa-specific PCs may be implicated in lipid and sterol regulation. Examples include the role of furin, PACE4, and PC5 in the inactivation of endothelial and lipoprotein lipases and in the processing of receptors such the lipoprotein-related receptor protein LRP1. On the other hand, it is very clear that SKI-1/S1P is directly implicated in the regulation of SREBPs activation and hence the synthesis of cholesterol and fatty acids. Finally, PCSK9, through degradation of the LDLR, indirectly contributes to the regulation of the levels of circulating LDL-C.
How can we envisage a drug design against the convertases implicated in regulating the levels of cholesterol and/or fatty acids? Concerning the role of furin, PACE4, and PC5 in the inactivation of lipases (Fig. 2), it would not be recommended to use an inhibitor of these enzymes, as this would likely result in a decreased level of HDL [37, 38]. This assumption should be verified by measuring lipase activity and HDL-C levels in knockout mice of either furin, PACE4, or PC5. As the knockouts furin [80] and PC5 [30] are embryonic lethal, it will be necessary to use conditional knockouts in either liver or endothelial cells to answer this question. In the case of SKI-1/S1P that activates SREBPs and/or PCSK9 that enhances the degradation of LDLR, a direct cell permeable functional inhibitor obtained through high throughput screens (HTS) of combinatorial libraries of nonpeptidic compounds may be successful. This could take the shape of in vitro assays screens with fluorogenic substrates or cell-based assays. The identification of “hits” would then be followed by medicinal chemistry methods to enhance the potency, efficacy, and kinetic bioavailability of the “hits” and drastically reduce their possible toxicity. As in the case of PCSK9, the enzyme is secreted as a tight binding complex with its inhibitory prosegment [10, 11, 85], it may be difficult to achieve an in vitro enzymatic activity. However, as addition of the PCSK9-prosegment complex outside cells allows its internalization into endosomes and results in a functional protein [18, 64], a cell-based functional assay using the level of LDLR as end point would allow HTS for an inhibitor of the function of PCSK9 or its more active D374Y mutant [11, 45] on the degradation of endogenous LDLR in either HuH7, HepG2, or HEK293 cells (and hence higher levels of cell-surface LDLR). For example we could use either automated FACS with a monoclonal antibody (mAb) to LDLR, or fluorescent LDLR-mAb or even DiI-LDL ligand (Fig. 8). As heterozygotes lacking 50% of the functional PCSK9 already show marked reduction in circulating LDL-C [21, 44], it may not be necessary to reduce the levels or activity of PCSK9 by more than 70–80% to achieve the desired effect.
Although PC-based hypolipidemic treatments are still in their infancy, the future will tell whether modulating the levels or activity of some of these convertases may represent viable therapeutic approaches that when combined with the other drugs, may well prove to be very beneficial in treating cardiovascular disorders.
References
Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156
Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabes JP (2005) Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 26:497
Anderson ED, Molloy SS, Jean F, Fei H, Shimamura S, Thomas G (2002) The ordered and compartment-specfific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. J Biol Chem 277:12879–12890
Attie AD (2004) The mystery of PCSK9. Arterioscler Thromb Vasc Biol 24:1337–1339
Attie AD, Seidah NG (2005) Dual regulation of the LDL receptor-some clarity and new questions. Cell Metab 1:290–292
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366:1267–1278
Barrett AJ (2004) Bioinformatics of proteases in the MEROPS database. Curr Opin Drug Discov Devel 7:334–341
Basak A, Chretien M, Seidah NG (2002) A rapid fluorometric assay for the proteolytic activity of SKI-1/S1P based on the surface glycoprotein of the hemorrhagic fever Lassa virus. FEBS Lett 514:333–339
Bassi DE, Fu J, Lopez DC, Klein-Szanto AJ (2005) Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol Carcinog 44:151–161
Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chretien M, Prat A, Seidah NG (2004) NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 279:48865–48875
Benjannet S, Rhainds D, Hamelin J, Nassoury N, Seidah NG (2006) The proprotein convertase PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. J Biol Chem 281:30561–30572
Berge KE, Ose L, Leren TP (2006) Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol 26:1094–10100
Bergeron E, Basak A, Decroly E, Seidah NG (2003) Processing of alpha4 integrin by the proprotein convertases: histidine at position P6 regulates cleavage. Biochem J 373:475–484
Briel M, Nordmann AJ, Bucher HC (2005) Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses. Curr Opin Lipidol 16:601–605
Broedl UC, Jin W, Rader DJ (2004) Endothelial lipase: a modulator of lipoprotein metabolism upregulated by inflammation. Trends Cardiovasc Med 14:202–206
Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340
Brown MS, Goldstein JL (2006) Biomedicine. Lowering LDL—not only how low, but how long? Science 311:1721–1723
Cameron J, Holla OL, Ranheim T, Kulseth MA, Berge KE, Leren TP (2006) Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet 15:1551–1558
Carmena R, Duriez P, Fruchart JC (2004) Atherogenic lipoprotein particles in atherosclerosis. Circulation 109:III2–III7
Cheng D, Espenshade PJ, Slaughter CA, Jaen JC, Brown MS, Goldstein JL (1999) Secreted site-1 protease cleaves peptides corresponding to luminal loop of sterol regulatory element-binding proteins. J Biol Chem 274:22805–22812
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37:161–165
Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux AL, Grefhorst A, Staels B, Krempf M (2006) Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element binding protein 1c. J Biol Chem 281:6211–6218
Creemers JW, Siezen RJ, Roebroek AJ, Ayoubi TA, Huylebroeck D, Van de Ven WJ (1993) Modulation of furin-mediated proprotein processing activity by site-directed mutagenesis. J Biol Chem 268:21826–21834
De Bie I, Marcinkiewicz M, Malide D, Lazure C, Nakayama K, Bendayan M, Seidah NG (1996) The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments. J Cell Biol 135:1261–1275
Dickson MC, Slager HG, Duffie E, Mummery CL, Akhurst RJ (1993) RNA and protein localisations of TGF beta 2 in the early mouse embryo suggest an involvement in cardiac development. Development 117:625–639
Dubois CM, Blanchette F, Laprise MH, Leduc R, Grondin F, Seidah NG (2001) Evidence that furin is an authentic transforming growth factor-beta1-converting enzyme. Am J Pathol 158:305–316
Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (2004) Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 24:1454–1459
Dunker N, Krieglstein K (2000) Targeted mutations of transforming growth factor-beta genes reveal important roles in mouse development and adult homeostasis. Eur J Biochem 267:6982–6988
Elagoz A, Benjannet S, Mammarbassi A, Wickham L, Seidah NG (2002) Biosynthesis and cellular trafficking of the convertase SKI-1/S1P: ectodomain shedding requires SKI-1 activity. J Biol Chem 277:11265–11275
Essalmani R, Hamelin J, Marcinkiewicz J, Chamberland A, Mbikay M, Chretien M, Seidah NG, Prat A (2006) Deletion of the gene encoding proprotein convertase 5/6 causes early embryonic lethality in the mouse. Mol Cell Biol 26:354–361
Falchi M, Andrew T, Snieder H, Swaminathan R, Surdulescu GL, Spector TD (2005) Identification of QTLs for serum lipid levels in a female sib-pair cohort: a novel application to improve the power of two-locus linkage analysis. Hum Mol Genet 14:2971–2979
Fasano T, Cefalu AB, Di Leo E, Noto D, Pollaccia D, Bocchi L, Valenti V, Bonardi R, Guardamagna O, Averna M, Tarugi P (2007) A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol (in press)
Gotto AM Jr, Pownall HJ, Havel RJ (1986) Introduction to the plasma lipoproteins. Methods Enzymol 128:3–41
Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR (2007) The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis (in press)
Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100:12027–12032
Jean F, Stella K, Thomas L, Liu G, Xiang Y, Reason AJ, Thomas G (1998) Alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc Natl Acad Sci USA 95:7293–7298
Jin W, Fuki IV, Seidah NG, Benjannet S, Glick JM, Rader DJ (2005) Proprotein covertases are responsible for proteolysis and inactivation of endothelial lipase. J Biol Chem 280:36551–36559
Jin W, Millar JS, Broedl U, Glick JM, Rader DJ (2003) Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo. J Clin Invest 111:357–362
Jonas A (2002) Lipoprotein structure. In: Vance DE, Vance JE (eds) Biochemistry of lipids, lipoproteins and membranes. Elsevier, Amsterdam, pp 483–504
Khatib AM, Siegfried G, Chretien M, Metrakos P, Seidah NG (2002) Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol 160:1921–1935
Khatib AM, Siegfried G, Prat A, Luis J, Chretien M, Metrakos P, Seidah NG (2001) Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions. J Biol Chem 276:30686–30693
Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H (2002) Angptl3 regulates lipid metabolism in mice. Nat Genet 30:151–157
Koster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D, Qiu Y, Fraser CC, Yang DD, Heuer JG, Jaskunas SR, Eacho P (2005) Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 146:4943–4950
Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH (2006) A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78:410–422
Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, Anderson NN, Ho YK, Hammer RE, Horton JD (2006) Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and inlivers of parabiotic mice. J Clin Invest 116:2995–3005
Lalanne F, Lambert G, Amar MJ, Chetiveaux M, Zair Y, Jarnoux AL, Ouguerram K, Friburg J, Seidah NG, Brewer HB Jr, Krempf M, Costet P (2005) Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J Lipid Res 46:1312–1319
Lambert G, Jarnoux AL, Pineau T, Pape O, Chetiveaux M, Laboisse C, Krempf M, Costet P (2006) Fasting induces hyperlipidemia in mice overexpressing PCSK9: lack of modulation of VLDL hepatic output by the LDLr. Endocrinology 147:4985–4995
Leduc R, Molloy SS, Thorne BA, Thomas G (1992) Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage. J Biol Chem 267:14304–14308
Lenz O, ter Meulen J, Klenk HD, Seidah NG, Garten W (2001) The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. Proc Natl Acad Sci USA 98:12701–12705
Leren TP (2004) Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 65:419–422
Lewis GF, Rader DJ (2005) New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 96:1221–1232
Lissitzky JC, Luis J, Munzer JS, Benjannet S, Parat F, Chretien M, Marvaldi J, Seidah NG (2000) Endoproteolytic processing of integrin pro-alpha subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7. Biochem J 346(Pt 1):133–138
Lu R, Yang P, O’Hare P, Misra V (1997) Luman, a new member of the CREB/ATF family, binds to herpes simplex virus VP16-associated host cellular factor. Mol Cell Biol 17:5117–5126
Lusson J, Vieau D, Hamelin J, Day R, Chretien M, Seidah NG (1993) cDNA structure of the mouse and rat subtilisin/kexin-like PC5: a candidate proprotein convertase expressed in endocrine and nonendocrine cells. Proc Natl Acad Sci USA 90:6691–6695
Maxwell KN, Breslow JL (2004) Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 101:7100–7105
Maxwell KN, Fisher EA, Breslow JL (2005) Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA 102:2069–2074
Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 44:2109–2119
Mercure C, Jutras I, Day R, Seidah NG, Reudelhuber TL (1996) Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex. Hypertension 28:840–846
Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P, Leighton PA, Goodrich LV, Lu X, Avery BJ, Tate P, Dill K, Pangilinan E, Wakenight P, Tessier-Lavigne M, Skarnes WC (2001) Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet 28:241–249
Molloy SS, Thomas L, VanSlyke JK, Stenberg PE, Thomas G (1994) Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface. EMBO J 13:18–33
Mouchantaf R, Watt HL, Sulea T, Seidah NG, Alturaihi H, Patel YC, Kumar U (2004) Prosomatostatin is proteolytically processed at the amino terminal segment by subtilase SKI-1. Regul Pept 120:133–140
Nakagawa T, Hosaka M, Torii S, Watanabe T, Murakami K, Nakayama K (1993) Identification and functional expression of a new member of the mammalian Kex2-like processing endoprotease family: its striking structural similarity to PACE4. J Biochem (Tokyo) 113:132–135
Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK (2005) Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 25:2654–2660
Nassoury N, Blasiole D, Tebon-Oler A, Benjannet S, Poupon VSM, McPherson P, Attie AD, Prat A, Seidah NG (2007) The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic (in press)
Nour N, Basak A, Chretien M, Seidah NG (2003) Structure-function analysis of the prosegment of the proprotein convertase PC5A. J Biol Chem 278:2886–2895
Nour N, Mayer G, Mort JS, Salvas A, Mbikay M, Morrison CJ, Overall CM, Seidah NG (2005) The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases. Mol Biol Cell 16:5215–5226
Olsson AG (2006) Are lower levels of low-density lipoprotein cholesterol beneficial? a review of recent data. Curr Atheroscler Rep 8:382–389
Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M (2004) Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler Thromb Vasc Biol 24:1448–1453
Overall CM, Kleifeld O (2006) Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer 94:941–946
Park SW, Moon YA, Horton JD (2004) Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 279:50630–50638
Pasquato A, Pullikotil P, Asselin MC, Vacatello M, Paolillo L, Ghezzo F, Basso F, Di Bello C, Dettin M, Seidah NG (2006) The proprotein convertase SKI-1/S1P: in vitro analysis of lassa virus glycoprotein-derived substrates and ex vivo validation of irreversible peptide inhibitors. J Biol Chem 281:23471–23481
Pisciotta L, Oliva CP, Cefalu AB, Noto D, Bellocchio A, Fresa R, Cantafora A, Patel D, Averna M, Tarugi P, Calandra S, Bertolini S (2006) Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis 186:433–440
Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (2003) Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 4:544–558
Pullikotil P, Vincent M, Nichol ST, Seidah NG (2004) Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P: processing of SREBP-2, ATF6, and a viral glycoprotein. J Biol Chem 279:17338–17347
Raman M, Cobb MH (2006) TGF-beta regulation by Emilin1: new links in the etiology of hypertension. Cell 124:893–895
Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD (2005) Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA 102:5374–5379
Reudelhuber TL, Ramla D, Chiu L, Mercure C, Seidah NG (1994) Proteolytic processing of human prorenin in renal and non-renal tissues. Kidney Int 46:1522–1524
Roebroek AJ, Schalken JA, Bussemakers MJ, van Heerikhuizen H, Onnekink C, Debruyne FM, Bloemers HP, Van de Ven WJ (1986) Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene. Mol Biol Rep 11:117–125
Roebroek AJ, Taylor NA, Louagie E, Pauli I, Smeijers L, Snellinx A, Lauwers A, Van de Ven WJ, Hartmann D, Creemers JW (2004) Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem 279:53442–53450
Roebroek AJ, Umans L, Pauli IG, Robertson EJ, van Leuven F, Van de Ven WJ, Constam DB (1998) Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. Development 125:4863–4876
Sakai J, Rawson RB, Espenshade PJ, Cheng D, Seegmiller AC, Goldstein JL, Brown MS (1998) Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell 2:505–514
Salvas A, Benjannet S, Reudelhuber TL, Chretien M, Seidah NG (2005) Evidence for proprotein convertase activity in the endoplasmic reticulum/early Golgi. FEBS Lett 579:5621–5625
Scamuffa N, Calvo F, Chretien M, Seidah NG, Khatib AM (2006) Proprotein convertases: lessons from knockouts. FASEB J 20:1954–1963
Schlombs K, Wagner T, Scheel J (2003) Site-1 protease is required for cartilage development in zebrafish. Proc Natl Acad Sci USA 100:14024–14029
Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003) The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 100:928–933
Seidah NG, Chretien M (1999) Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res 848:45–62
Seidah NG, Chretien M, Day R (1994) The family of subtilisin/kexin like pro-protein and pro-hormone convertases: divergent or shared functions. Biochimie 76:197–209
Seidah NG, Khatib AM, Prat A (2006) The proprotein convertases and their implication in sterol and/or lipid metabolism. Biol Chem 387:871–877
Seidah NG, Mowla SJ, Hamelin J, Mamarbachi AM, Benjannet S, Toure BB, Basak A, Munzer JS, Marcinkiewicz J, Zhong M, Barale JC, Lazure C, Murphy RA, Chretien M, Marcinkiewicz M (1999) Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proc Natl Acad Sci USA 96:1321–1326
Seidah NG, Prat A (2002) Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem 38:79–94
Shioji K, Mannami T, Kokubo Y, Inamoto N, Takagi S, Goto Y, Nonogi H, Iwai N (2004) Genetic variants in PCSK9 affect the cholesterol level in Japanese. J Hum Genet 49:109–114
Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chretien M, Seidah NG, Khatib AM (2003) The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest 111:1723–1732
Siegfried G, Basak A, Prichett-Pejic W, Scamuffa N, Ma L, Benjannet S, Veinot JP, Calvo F, Seidah N, Khatib AM (2005) Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. Oncogene 24:6925–6935
Siegfried G, Khatib AM, Benjannet S, Chretien M, Seidah NG (2003) The proteolytic processing of pro-platelet-derived growth factor-A at RRKR(86) by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity. Cancer Res 63:1458–1463
Srour N, Lebel A, McMahon S, Fournier I, Fugere M, Day R, Dubois CM (2003) TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity. FEBS Lett 554:275–283
Stawowy P, Blaschke F, Kilimnik A, Goetze S, Kallisch H, Chretien M, Marcinkiewicz M, Fleck E, Graf K (2002) Proprotein convertase PC5 regulation by PDGF-BB involves PI3-kinase/p70(s6)-kinase activation in vascular smooth muscle cells. Hypertension 39:399–404
Stawowy P, Fleck E (2005) Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. J Mol Med 83:865–875
Stawowy P, Graf K, Goetze S, Roser M, Chretien M, Seidah NG, Fleck E, Marcinkiewicz M (2003) Coordinated regulation and colocalization of alphav integrin and its activating enzyme proprotein convertase PC5 in vivo. Histochem Cell Biol 119:239–245
Stawowy P, Kallisch H, Kilimnik A, Margeta C, Seidah NG, Chretien M, Fleck E, Graf K (2004) Proprotein convertases regulate insulin-like growth factor 1-induced membrane-type 1 matrix metalloproteinase in VSMCs via endoproteolytic activation of the insulin-like growth factor-1 receptor. Biochem Biophys Res Commun 321:531–538
Stawowy P, Kallisch H, Veinot JP, Kilimnik A, Prichett W, Goetze S, Seidah NG, Chretien M, Fleck E, Graf K (2004) Endoproteolytic activation of alpha(v) integrin by proprotein convertase PC5 is required for vascular smooth muscle cell adhesion to vitronectin and integrin-dependent signaling. Circulation 109:770–776
Stawowy P, Marcinkiewicz J, Graf K, Seidah N, Chretien M, Fleck E, Marcinkiewicz M (2001) Selective expression of the proprotein convertases furin, pc5, and pc7 in proliferating vascular smooth muscle cells of the rat aorta in vitro. J Histochem Cytochem 49:323–332
Stawowy P, Margeta C, Kallisch H, Seidah NG, Chretien M, Fleck E, Graf K (2004) Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-beta1 involves furin-convertase. Cardiovasc Res 63:87–97
Stirling J, O’Hare P (2006) CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P. Mol Biol Cell 17:413–426
Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK (2005) Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet 14:1161–1169
Tadros H, Seidah NG, Chretien M, Mbikay M (2002) Genetic mapping of the gene for SKI-1/S1P protease (locus symbol Mbtps1) to mouse chromosome 8. DNA Seq 13:109–111
Takahashi S, Nakagawa T, Kasai K, Banno T, Duguay SJ, Van de Ven WJ, Murakami K, Nakayama K (1995) A second mutant allele of furin in the processing-incompetent cell line, LoVo. Evidence for involvement of the homo B domain in autocatalytic activation. J Biol Chem 270:26565–26569
Tall AR (2006) Protease variants, LDL, and coronary heart disease. N Engl J Med 354:1310–1312
Taylor NA, Van de Ven WJ, Creemers JW (2003) Curbing activation: proprotein convertases in homeostasis and pathology. FASEB J 17:1215–1227
Thomas G (2002) Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3:753–766
Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM (2004) A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 114:349–353
Toth PP, Davidson MH (2005) Cholesterol absorption blockade with ezetimibe. Curr Drug Targets Cardiovasc Haematol Disord 5:455–462
Toure BB, Munzer JS, Basak A, Benjannet S, Rochemont J, Lazure C, Chretien M, Seidah NG (2000) Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. J Biol Chem 275:2349–2358
Twisk J, Gillian-Daniel DL, Tebon A, Wang L, Barrett PH, Attie AD (2000) The role of the LDL receptor in apolipoprotein B secretion. J Clin Invest 105:521–532
Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD (2001) Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc Natl Acad Sci USA 98:13607–13612
Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364
Zacchigna L, Vecchione C, Notte A, Cordenonsi M, Dupont S, Maretto S, Cifelli G, Ferrari A, Maffei A, Fabbro C, Braghetta P, Marino G, Selvetella G, Aretini A, Colonnese C, Bettarini U, Russo G, Soligo S, Adorno M, Bonaldo P, Volpin D, Piccolo S, Lembo G, Bressan GM (2006) Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell 124:929–942
Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79:514–523
Zheng M, Streck RD, Scott RE, Seidah NG, Pintar JE (1994) The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. J Neurosci 14:4656–4673
Acknowledgements
We would like to thank Brigitte Mary for her secretarial help. This work was supported by grants from the CIHR (MOP 36496, MGP-44363, and Canada chair no. 201652) and by a generous gift from the Strauss foundation.
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Seidah, N.G., Prat, A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J Mol Med 85, 685–696 (2007). https://doi.org/10.1007/s00109-007-0172-7
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DOI: https://doi.org/10.1007/s00109-007-0172-7