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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.

Key Points

  • In addition to their role in nutrient digestion, proteases in the gastrointestinal tract regulate the availability and activity of growth factors, cytokines and extracellular matrix proteins

  • Intestinal epithelial cell biology and function might be controlled by interactions between proteases and their inhibitors and receptors, which are expressed by diverse cells of the intestinal epithelium

  • There are numerous mechanisms in place to ensure that a protease balance is achieved (e.g. synthesis as inactive zymogens, spatial and temporal compartmentalization and termination of activity), because unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions

  • Enteric microbes and parasites can hijack host proteolytic pathways through 'pathogen host mimicry'

  • To achieve a better understanding of gastrointestinal physiology and disease, it is fundamental that we understand the mechanisms by which proteases function and the ways they are regulated in the complex microenvironment of the cells of the gastrointestinal tract

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Figure 1: Protease pools relevant to intestinal mucosal pathophysiology
Figure 2: Examples of protease signaling and inter-receptor crosstalk on the cell membrane

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Acknowledgements

Work by the authors was supported in part by grants from the National Institutes of Health: DK48373 (AF), AI/DK49316 (TSD), CA098369 and HL084387 (TMA), AI18797 (SNV), and DK45496 (CS).

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Correspondence to Alessio Fasano.

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AF and SV have economic interests in Alba Therapeutics, a company that works on the treatment of autoimmune diseases, including type 1 diabetes and celiac disease. The other authors declared they have no competing interests.

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Antalis, T., Shea-Donohue, T., Vogel, S. et al. Mechanisms of Disease: protease functions in intestinal mucosal pathobiology. Nat Rev Gastroenterol Hepatol 4, 393–402 (2007). https://doi.org/10.1038/ncpgasthep0846

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