Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases

Emma L. Carroll, Mariarca Bailo, James A. Reihill, Anne Crilly, John C. Lockhart, Gary J. Litherland, Fionnuala T. Lundy, Lorcan P. McGarvey, Mark A. Hollywood, S. Lorraine Martin*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

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Abstract

Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets.
Original languageEnglish
Article numbere5817
Number of pages22
JournalInternational Journal of Molecular Sciences
Volume22
Issue number11
DOIs
Publication statusPublished - 29 May 2021

Keywords

  • trypsin-like proteases
  • ENaC
  • PAR2
  • airway dehydration
  • inflammation
  • virus activation
  • influenza
  • SARS-CoV-2
  • COVID-19
  • serpins
  • protease inhibitors

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