The C-Terminal Sequence of Several Human Serine Proteases Encodes Host Defense Functions

Abstract

Serine proteases of the S1 family have maintained a common structure over an evolutionary span of more than one billion years, and evolved a variety of substrate specificities and diverse biological roles, involving digestion and degradation, blood clotting, fibrinolysis and epithelial homeostasis. We here show that a wide range of C-terminal peptide sequences of serine proteases, particularly from the coagulation and kallikrein systems, share characteristics common with classical antimicrobial peptides of innate immunity. Under physiological conditions, these peptides exert antimicrobial effects as well as immunomodulatory functions by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, selected peptides are protective against lipopolysaccharide-induced shock. Moreover, these S1-derived host defense peptides exhibit helical structures upon binding to lipopolysaccharide and also permeabilize liposomes. The results uncover new and fundamental aspects on host defense functions of serine proteases present particularly in blood and epithelia, and provide tools for the identification of host defense molecules of therapeutic interest.

Collagen VI Encodes Antimicrobial Activity: Novel Innate Host Defense Properties of the Extracellular Matrix

“…Electron microscopy showed that collagen VI induces a membrane permeabilization effect similar to the ‘classical’ antimicrobial cathelicidin peptide LL-37 [24,25,26]. Our data do not, however, demonstrate the exact killing mechanism by collagen VI because secondary metabolic effects may trigger bacterial death and membrane disruption.…”

Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

“…It contributes to activation of the extrinsic coagulation pathway because of its capacity to cleave the tissue factor pathway inhibitor (TFPI), which was shown to obtain antibacterial activity on proteolytic processing (45,46). Similarly, many other coagulation factors, including factor X and prothrombin, contain a catalytic domain at their C terminus with antimicrobial activity after proteolytic processing (47). To date, it is unknown whether coagulation plays a protective role against a Y. pseudotuberculosis infection.…”

Kallikreins – The melting pot of activity and function

“…Also KLK8 has been described as kallikrein expressed by keratinocytes, with potential function in skin barrier proteolytic function [89]. More detailed study indicate the C-terminal fragment of KLK8 as one of the peptides involved in skin innate immunity [90]. …”