Mechanisms of disease: protease functions in intestinal mucosal pathobiology

Abstract

Of all our organ systems, the gastrointestinal tract contains the highest levels of endogenous and exogenous proteases (also known as proteinases and peptidases); however, our understanding of their functions and interactions within the gastrointestinal tract is restricted largely to nutrient digestion. The gut epithelium is a sensor of the luminal environment, not only controlling digestive, absorptive and secretory functions, but also relaying information to the mucosal immune, vascular and nervous systems. These functions involve a complex array of cell types that elaborate growth factors, cytokines and extracellular matrix (ECM) proteins, the activity and availability of which are regulated by proteases. Proteolytic activity must be tightly regulated in the face of diverse environmental challenges, because unrestrained or excessive proteolysis leads to pathological gastrointestinal conditions. Moreover, enteric microbes and parasites can hijack proteolytic pathways through 'pathogen host mimicry'. Understanding how the protease balance is maintained and regulated in the intestinal epithelial cell microenvironment and how proteases contribute to physiological and pathological outcomes will undoubtedly contribute to the identification of new potential therapeutic targets for gastrointestinal diseases.

Figure 1

Protease pools relevant to intestinal mucosal pathophysiology. The intestinal epithelial microenvironment generated by the pool of endogenous and exogenous proteases is finely controlled. By controlling the intestinal epithelial microenvironment, appropriate physiological enterocyte function is maintained and pathological situations such inflammation, injury, and tumorigenesis can be reacted to. A few representative examples of the many proteases present in the gut are shown. Abbreviations: APC, antigen-presenting cell; BFT, Bacteroides fragilis zinc-dependent metalloproteinase enterotoxin; DPP IV, dipeptidyl peptidase 4; ECM, extracellular matrix; IEC, intestinal epithelial cell; MMP, matrix metalloproteinase; T_H, T helper cell; T_REG, T regulatory cell.

Figure 2

Examples of protease signaling and inter-receptor crosstalk on the cell membrane. (1) Protease zymogen cascades. Many proteases are synthesized as inactive precursors that are converted to their active form by limited proteolysis. For example, zymogen conversions involving the coagulation cascade result in cleavage and conversion of prothrombin to active thrombin at the cell surface. (2) Protease signalling by activation of PARs. Proteolytic cleavage of the extracellular amino-terminal domain of PARs unmasks a new amino terminus that binds to the body of the PAR itself and acts as a ‘tethered ligand’, inducing G-protein-coupled intracellular signaling responses. The PAR can be disabled by proteolytic cleavage downstream of the tethered ligand sequence. (3) There is crosstalk between GPCR signaling pathways and other cellular signaling pathways via ligand-dependent signal transactivation. GPCR signaling induces membrane metalloproteinase (ADAM) activation and proteolytic release of EGF-like ligands, inducing phosphorylation and signaling via the EGF-receptor tyrosine kinase., Abbreviations: ADAM, a disintegrin and metalloproteinase domain; EGF, epidermal growth factor; GPCR, G-protein-coupled receptor; L, ligand; P, phosphate; PAR, protease-activated receptor.