Proprotein convertase 7 (PCSK7) reduces apoA‐V levels

Abstract

The locus of the human proprotein convertase subtilisin-kexin type-7 (PC7) gene (PCSK7) is on chromosome 11q23.3 close to the gene cluster APOA5/APOA4/APOC3/APOA1, a region implicated in the regulation of lipoprotein metabolism. A GWAS reported the association of PCSK7 SNPs with plasma triglyceride (TG), and exome sequencing of African Americans revealed the association of a low-frequency coding variant of PC7 (R504H; SNP rs142953140) with a~30% TG reduction. Another PCSK7 SNP rs508487 is in linkage disequilibrium with a promoter variant of the liver-derived apolipoprotein A-V (apoA-V), an indirect activator of the lipoprotein lipase (LpL), and is associated with elevated TG levels. We thus hypothesized that PC7 regulates the levels/activity of apoA-V. Studies in the human hepatic cell line HuH7 revealed that wild-type (WT) PC7 and its endoplasmic reticulum (ER)-retained forms bind to and enhance the degradation of human apoA-V in acidic lysosomes in a nonenzymatic fashion. PC7-induced degradation of apoA-V is inhibited by bafilomycin A1 and the alkalinizing agents: chloroquine and NH 4 Cl. Thus, the PC7-induced apoA-V degradation implicates an ER-lysosomal communication inhibited by bafilomycin A1. In vitro, the natural R504H mutant enhances PC7 Ser 505 phosphorylation at the structurally exposed Ser-X-Glu 507 motif recognized by the secretory kinase Fam20C. Co-expression of the phosphomimetic PC7-S505E with apoA-V resulted in lower degradation compared to WT, suggesting that Ser 505 phosphorylation of PC7 lowers TG levels via reduced apoA-V degradation. In agreement, in Pcsk7 À/À mice fed high-fat diet, plasma apoA-V levels and adipocyte LpL activity are increased, providing an in vivo mechanistic link for a role of liver PC7 in enhanced TG storage in adipocytes.

The rs508487, rs236911, and rs236918 Genetic Variants of the Proprotein Convertase Subtilisin–Kexin Type 7 (PCSK7) Gene Are Associated with Acute Coronary Syndrome and with Plasma Concentrations of HDL-Cholesterol and Triglycerides

“…In the present work, we studied three polymorphisms (rs508487 T/C, rs236911 C/A, and rs236918 C/G) located on the PCSK7 gene that encodes to the human PCSK7 proprotein. This protein has been implicated in the regulation of apoA-5 and has been associated with a higher triglyceride concentration [3,[6][7][8][9]. In our study, we reported the association of the rs508487 T, rs236911 C, and rs236918 C alleles with the risk of developing ACS.…”

“…Previous reports have suggested the role of the PCSK7 on plasma lipid levels [6,8,[10][11][12][13]. Therefore, in this study we first explored the potential association of rs508487 T/C, rs236911 C/A, and rs236918 C/G SNPs with total cholesterol, LDL-C, HDL-C, ratio LDL/HDL, and triglyceride plasma concentrations.…”

“…These proprotein convertases are related to the cleavage peptide bonds of various proteins and peptides in multiple subcellular compartments included in the secretory pathway [endoplasmic reticulum (ER), various Golgi cisternae, endosomes], which leads to the activation/inactivation of receptors, ligands, enzymes, viral glycoproteins, or growth factors [5]. Recent studies have shown that the human PCSK7 proprotein is implicated in the regulation of apolipoprotein A-5 (apoA-5) and is associated with a higher triglyceride concentration [6,7], both with an important role in the development of cardiovascular diseases [3,[8][9][10]. The PCSK7 proprotein is encoded by the PCSK7 gene, located in the q23.3 region of chromosome 11.…”

“…Genome-wide association studies (GWAS) have shown that some single nucleotide polymorphisms (SNPs) of the PCSK7 gene are associated with hypertriglyceridemia, with large effects on HDL-C and/or triglyceride levels [10][11][12][13]. Recent studies have associated three novel SNPs [PCSK7 nearGene-3 rs508487 T/C, PCSK7 intron 6 rs236911 C/A, and PCSK7 intron 9 rs236918 C/G] with an overexpression of the PCSK7 and hypertriglyceridemia [6,[10][11][12][13], as well as with the risk of developing atherosclerosis and liver disease [4,10].…”

Shedding of cancer susceptibility candidate 4 by the convertases PC7/furin unravels a novel secretory protein implicated in cancer progression

“…Coincidentally, this is the locus of PCSK7 that resides close to the gene-cluster APOA5/APOA4/APOC3/APOA1 , a region implicated in the regulation of lipoprotein metabolism (Supplementary Fig. S6 ) 53 .…”