Human airway trypsin-like protease (HAT) (HAT)

Human airway trypsin-like protease (HAT), also known as TMPRSS11D, is a type II transmembrane serine protease primarily expressed in the epithelial cells of the human respiratory tract, including the trachea and bronchi. It plays a vital role in maintaining airway surface liquid (ASL) homeostasis by proteolytically activating the epithelial sodium channel (ENaC), which promotes sodium and water reabsorption across the apical membrane. Beyond its physiological function in ion transport, HAT is a key mediator of airway inflammation and mucus hypersecretion through the activation of protease-activated receptor 2 (PAR2), contributing to the pathogenesis of chronic obstructive pulmonary disease (COPD) and cystic fibrosis. HAT has also been identified as a critical host cell protease that facilitates the entry of respiratory viruses, such as influenza A and SARS-CoV-2, by cleaving and activating their fusion proteins. Consequently, HAT is considered a significant therapeutic target for both chronic muco-obstructive lung diseases and viral infections. Serine protease inhibitors like camostat and nafamostat have been shown to inhibit HAT activity, offering a potential strategy to reduce ENaC overactivation and viral spread. However, achieving high selectivity for HAT over other structurally similar serine proteases remains a major challenge in drug development.

Other names

Transmembrane protease serine 11DTMPRSS11DAirway trypsin-like proteaseSerine protease 11D

Serine protease inhibition; Prevention of ENaC proteolytic activation; Inhibition of PAR2-mediated inflammatory signaling; Prevention of viral fusion protein cleavage