Abstract
Genome mining at the turn of the millennium uncovered a new family of type II transmembrane serine proteases (TTSPs) that comprises 17 members in humans and 19 in mice. TTSPs phylogenetically belong to one of four subfamilies: matriptase, hepsin/TMPRSS, corin and HAT/DESC. Whereas a wealth of information now has been gathered as to the physiological functions of members of the hepsin/TMPRSS, matriptase, and corin subfamilies of TTSPs, comparatively little is known about the functions of the HAT/DESC subfamily of proteases. Here we perform a combined expression and functional analysis of this TTSP subfamily. We show that the five human and seven murine HAT/DESC proteases are coordinately expressed, suggesting a level of functional redundancy. We also perform a comprehensive phenotypic analysis of mice deficient in two of the most widely expressed HAT/DESC proteases, TMPRSS11A and HAT, and show that the two proteases are dispensable for development, health, and long-term survival in the absence of external challenges or additional genetic deficits. Our comprehensive expression analysis and generation of TMPRSS11A- and HAT-deficient mutant mouse strains provide a valuable resource for the scientific community for further exploration of the HAT/DESC subfamily proteases in physiological and pathological processes.
Highlights
Among the more surprising discoveries emanating from systematic genome-mining at the turn of the millennium was the unveiling of a large new family of trypsin-like membrane-anchored serine proteases, subsequently named type II transmembrane serine proteases (TTSPs) [1]
Orthologs of all five human human airway trypsin-like serine protease (HAT)/DESC proteases are found in rodents, but rodents have two additional subfamily members (HAT-like 2 and HAT-like 3, encoded by, respectively, the Desc4 and Tmprss11c genes) that are not found in humans or chimpanzees
Tmprss11d displayed detectable expression in epithelia of the oral cavity, esophagus, and the anterior and posterior parts of the naris, whereas Tmprss11e and Tmprss11f displayed no signal, and no entries were available for Tmprss11a, Tmprss11b, Tmprss11c, and Desc4
Summary
Among the more surprising discoveries emanating from systematic genome-mining at the turn of the millennium was the unveiling of a large new family of trypsin-like membrane-anchored serine proteases, subsequently named type II transmembrane serine proteases (TTSPs) [1]. The TTSPs can be divided into four different subfamilies based on phylogenetic analysis of their serine protease domains, and this classification is supported by the composition of their stem regions and by the chromosomal localization of individual TTSP genes These are the matriptase subfamily, the hepsin/transmembrane protease serine (hepsin/TMPRSS) subfamily, the corin subfamily, and the human airway trypsin-like protease/differentially expressed in squamous cell carcinoma (HAT/DESC) subfamily [3,4,5]. This divergence of the primate and rodent HAT/DESC protease complement appears to be caused by gene loss in primates, rather than expansion of the rodent DESC cluster, as pseudogene orthologs of the rodent Desc and Tmprss11c genes are present in the human and chimpanzee genomes [8,10]
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