The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions

Abstract

The secretory proprotein convertase (PC) family comprises nine members: PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9. The first seven PCs cleave their substrates at single or paired basic residues, and SKI-1/S1P cleaves its substrates at non-basic residues in the Golgi. PCSK9 cleaves itself once, and the secreted inactive protease escorts specific receptors for lysosomal degradation. It regulates the levels of circulating LDL cholesterol and is considered a major therapeutic target in phase III clinical trials. In vivo, PCs exhibit unique and often essential functions during development and/or in adulthood, but certain convertases also exhibit complementary, redundant, or opposite functions.

Keywords: Cardiovascular Disease; Cell Surface Receptor; Cholesterol Metabolism; Furin-like Protease; Intracellular Processing; Low Density Lipoprotein (LDL); Precursor Processing; Proprotein Convertase; Protease; Secretory Proteins.

FIGURE 1.

Substrates of the PCs. A, these include precursors of hormones, growth factors, receptors, transcription factors, and surface glycoproteins. Cleavage at one or more PC sites usually results in the release of one or more bioactive moieties for soluble or membrane-bound precursors. Some of them are first cleaved by SKI-1/S1P and then processed a second time by S2P to release a cytosolic transcription factor that is then translocated into the nucleus. B, processing of polypeptide precursors by PCs results in the activation or inactivation of their substrates predominantly in a redundant or complementary fashion between PCs. However, unique activation or inactivation PC cleavages have also been reported, some of which are essential during embryonic development.

FIGURE 2.

Identification of PC substrates from the simple or complex phenotypes observed following modulation of their expression. The KO of a PC gene may result in an obvious phenotype (e.g. lack of a tail, as for PC5/6 KO) that would phenocopy the absence of a cognate substrate, as for PC5/6 and GDF11 (10). However, of the nine PCs, the loss of expression of four of them (furin, PACE4, PC5/6, and SKI-1/S1P) reveals phenotypes that are more complex and that lead to early death. The identification of in vivo substrates may require tissue-specific KO, double or triple KOs, and even transgenesis in some tissues.

FIGURE 3.

Cooperation and distinctiveness of PC1/3 and PC2 in the processing of three representative substrates. A, proinsulin processing in pancreatic β-cells implicates the two enzymes within the same cell, cleaving successively at two distinct preferred sites. B, pro-opiomelanocortin in two different lobes of the pituitary is cleaved to distinct end products according to the relative abundance of the enzymes in each lobe: ACTH and β-lipotropic hormone (β-LPH) in the AL and α-MSH, β-MSH, and β-endorphin (β-END) in the NIL. C, proglucagon is converted to glucagon (GLUC) in PC2-rich pancreatic α-cells and to GLP-1 and GLP-2 in PC1/3-rich intestinal L-cells. Note that after cleavage by PC1/3 and PC2, the C-terminally exposed basic residues must be trimmed off by carboxypeptidase E to generate fully active peptides.