Serpin functions in host-pathogen interactions

Abstract

Serpins are a broadly distributed superfamily of protease inhibitors that are present in all kingdoms of life. The acronym, serpin, is derived from their function as potent serine proteases inhibitors. Early studies of serpins focused on their functions in haemostasis since modulating serine proteases activities are essential for coagulation. Additional research has revealed that serpins function in infection and inflammation, by modulating serine and cysteine proteases activities. The aim of this review is to summarize the accumulating findings and current understanding of the functions of serpins in host-pathogen interactions, serving as host defense proteins as well as pathogenic factors. We also discuss the potential crosstalk between host and pathogen serpins. We anticipate that future research will elucidate the therapeutic value of this novel target.

Keywords: Host-pathogen interaction; Infection; Inflammation; Serine protease; Serpin.

Figure 1. Serpin structure and phylogenetic tree.

(A) Structure of the serpin alpha-1 antitrypsin. Human alpha-1 antitrypsin is representative of serpin structures. It contains α-helices (red), β-sheets (golden) and a reactive center loop (RCL, the upright blue region) (PDB: 3NE4). (B) Phylogenetic tree of serpin superfamily. The neighbour-joining tree is based on serpin protein sequences and different clades are represented by a single identifier (e.g., Antithrombin III, P01008), where possible. The phylogenetic analysis was performed using MEGA version 7.0. Analysis was done on 1,000 bootstrapped datasets and values of >50% are shown.

Figure 2. Representation of serpin-protease interaction.

(A) Proposed process of serpin-protease interaction. A serpin (magenta) interacts with targeted protease (blue), and the Michaelis-like complex of serpin and protease is formed. The complex either undergo peptide bond hydrolysis resulting in a kinetically trapped loop-inserted covalent complex (inhibitory pathway), or a cleaved serpin and free protease (non-inhibitory/substrate pathway). The cleaved and inserted RCL is highlighted in green. Serpin-protease complex is stable. Possibility of transition from covalent complex to cleaved form exists yet slim, since complex in vivo would be cleared long before complex decay could occur. (B) Structure of stable serpin- protease complex (PDB: 2D26). The complex is formed by serpin α1PI (magenta) and protease elastase (blue). The inserted RCL is highlighted in green.

Figure 3. Summary of serpin functions in host-pathogen interactions.

Hypothesis of protective mechanisms offered byhost serpins (on the left, blue), and pathogenic mechanisms exerted by pathogen-derived serpins (on the right, red). Host serpins may act directly or indirectly upon pathogen infections. The representative mechanisms include inhibiting pathogenic digestive proteases, promoting host antimicrobial peptide expression and so on. Pathogen-derived serpins also utilize various mechanisms and representative ones are listed.