Endoproteolysis in health and diseases—implications of proprotein convertases (PCs)

Abstract

Biologically active proteins and peptides are often generated by intracellular limited proteolysis of inactive precursors. This evolutionary ancient mechanism resulted in the elaboration of specific secretory enzymes and a tight regulation of their activities. Such phenomenon was initially identified more than 50 years ago by Hans Neurath [1] for the biosynthesis of trypsin and chymotrypsin. In the mid-1960s, it was recognized that peptide hormones were produced following an exquisite cleavage at pairs of basic amino acids [2, 3]. In the 1970s, the newly discovered neuropeptides including β-endorphin were found to be made with a similar mechanism [4]. The stage was set for the search of the suspected novel enzymes, a search that lasted until 1990. The identification of a family of serine proteinases of the subtilisin/kexin-type (proprotein convertases, PCs) and proof of their function(s) as intracellular dibasic processing enzymes, resolved this longstanding quest [5]. Over the last 15 years, the cumulative knowledge revealed that PCs processed a much wider array of secretary precursors than first anticipated, thus enlarging their biological importance. Among the nine known PCs, the first seven, namely, PC1, PC2, furin, PACE4, PC4, PC5, and PC7, suggest that they prefer to cleave precursors at Arg residues, and less so following Lys residues [6]. The last two to be identified (SKI-1/PC8, NARC/PC9) [7, 8] were surprisingly found to cleave at single or pairs of hydrophobic and/or small amino acids. Structure–function and cellular localization studies performed on all PCs exposed the functional complexity of their various domains. Thus, complex, well-orchestrated events regulate the temporal expression, tissue and intracellular localization, and the fine substrate specificity of these enzymes. Those studies also revealed that the number and varieties of substrates have markedly enlarged [6]. In addition to the hormonal a neurogastral peptides, they include growth factors and some of their receptors, viral envelope proteins, and even transcription factors. These hundreds of substrates clearly indicate that PCs are at the center of a variety of for normal physiological processes while being implicated in the pathophysiology of multiple illnesses. Although suspected early on [9], medical applications are only now beginning to take shape and it is hoped that in the future these would lead to novel rational therapeutical approaches in a number of pathologies including neurological dysfunctions, cardiovascular, metabolic, and proliferative diseases as well as opportunistic pathogenic infections and cholesterol metabolism [10]. In view of such developments, the editor of this journal invited us to coedit a series of articles on their clinical relevance. With the editorial help of our colleagues Nabil Seidah, Dominique Bataille, and Majambu M. Mbikay, we will publish in the next issues a series of articles that will present overviews on the implications of PCs in disorders as varied as obesity and diabetes, cancer and atherosclerosis, familial hypercholesterolemia, Alzheimer disease, and viral infections such as AIDS/HIV, severe acute respiratory syndrome (SARS)/CoV.