The Role of Proprotein Convertases in the Regulation of the Function of Immune Cells in the Oncoimmune Response.

Mélanie Rose,Michel Salzet,Marie Duhamel,Franck Rodet

doi:10.3389/fimmu.2021.667850

Abstract

Proprotein convertases (PC) are a family of 9 serine proteases involved in the processing of cellular pro-proteins. They trigger the activation, inactivation or functional changes of many hormones, neuropeptides, growth factors and receptors. Therefore, these enzymes are essential for cellular homeostasis in health and disease. Nine PC subtilisin/kexin genes (PCSK1 to PCSK9) encoding for PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P and PCSK9 are known. The expression of PC1/3, PC2, PC5/6, Furin and PC7 in lymphoid organs such as lymph nodes, thymus and spleen has suggested a role for these enzymes in immunity. In fact, knock-out of Furin in T cells was associated with high secretion of pro-inflammatory cytokines and autoantibody production in mice. This suggested a key role for this enzyme in immune tolerance. Moreover, Furin through its proteolytic activity, regulates the suppressive functions of Treg and thus prevents chronic inflammation and autoimmune diseases. In macrophages, Furin is also involved in the regulation of their inflammatory phenotype. Similarly, PC1/3 inhibition combined with TLR4 stimulation triggers the activation of the NF-κB signaling pathway with an increased secretion of pro-inflammatory cytokines. Factors secreted by PC1/3 KD macrophages stimulated with LPS exert a chemoattractive effect on naive auxiliary T lymphocytes (Th0) and anti-tumoral activities. The link between TLR and PCs is thus very important in inflammatory response regulation. Furin regulates TL7 and TLR8 processing and trafficking whereas PC1/3 controls TLR4 and TLR9 trafficking. Since PC1/3 and Furin are key regulators of both the innate and adaptive immune responses their inhibition may play a major role in oncoimmune therapy. The role of PCs in the oncoimmune response and therapeutic strategies based on PCs inhibition are proposed in the present review.

Highlights

The proteome is illustrated by its great complexity
It was demonstrated that the antiviral activity of TLR7 in human THP1 macrophages, B cells and dendritic cells depended on its proteolytic cleavage by furin in the endosomes [34]
In PC1/3 KD macrophages treated with CpG-ODN, TLR9 clustered in multivesicular bodies leading to a quicker activation of the NF-kB signaling pathway [29]

Summary

INTRODUCTION

The proteome is illustrated by its great complexity. Each protein can undergo post-translational modifications which regulate their function, location, activity and structure. Several studies have shown that PCs regulated the functions of TLRs to control the activity of immune cells In this context, it was demonstrated that the antiviral activity of TLR7 in human THP1 macrophages, B cells and dendritic cells depended on its proteolytic cleavage by furin in the endosomes [34]. In PC1/3 KD macrophages treated with CpG-ODN, TLR9 clustered in multivesicular bodies leading to a quicker activation of the NF-kB signaling pathway [29] All these results showed that PCs, especially furin and PC1/ 3, are central in the processing, maturation and biological activity of TLRs across cell types and species. The reprogrammation of tumor-associated macrophages by PCs inhibition has been shown to stably decrease their immunosuppressive properties They could be important to enhance T lymphocytes activities (Figure 5). A phase III clinical trial demonstrated that inhibition of PCSK9 in pediatric patients with heterozygous familial hypercholesterolemia reduced the LDL cholesterol level and other lipid variables (ClinicalTrials.gov Identifier: NCT02392559) [64]

CONCLUSION

ETHICS STATEMENT