The Serine Protease Marapsin Is Expressed in Stratified Squamous Epithelia and Is Up-regulated in the Hyperproliferative Epidermis of Psoriasis and Regenerating Wounds

Abstract

The trypsin-like serine protease marapsin is a member of the large protease gene cluster at human chromosome 16p13.3, which also contains the structurally related proteases testisin, tryptase ⑀, tryptase ␥, and EOS. To gain insight into the biological functions of marapsin, we undertook a detailed gene expression analysis. It showed that marapsin expression was restricted to tissues containing stratified squamous epithelia and was absent or only weakly expressed in all other tissues, including the pancreas. Marapsin was constitutively expressed in nonkeratinizing stratified squamous epithelia of human esophagus, tonsil, cervix, larynx, and cornea. In the keratinizing stratified squamous epidermis of skin, however, its expression was induced only during epidermal hyperproliferation, such as in psoriasis and in murine wound healing. In fact, marapsin was the second most strongly up-regulated protease in psoriatic lesions, where expression was localized to the upper region of the hyperplastic epidermis. Similarly, in the hyperproliferative epithelium of regenerating murine skin wounds, marapsin localized to the suprabasal layers, where keratinocytes undergo squamous differentiation. The transient up-regulation of marapsin, which closely correlated with re-epithelialization, was virtually absent in a genetic mouse model of delayed wound closure. These results suggested a function during the process of re-epithelialization. Furthermore, in reconstituted human epidermis, a model system of epidermal differentiation, members of the IL-20 subfamily of cytokines, such as IL-22, induced marapsin expression. Consistent with a physiologic role in marapsin regulation, IL-22 was also strongly expressed in re-epithelializing skin wounds. Marapsin's restricted expression, localization, and cytokine-inducible expression suggest a role in the terminal differentiation of keratinocytes in hyperproliferating squamous epithelia.Marapsin (PRSS27; also known as pancreasin) is a trypsinlike serine protease and member of the large serine protease gene cluster at human chromosome 16p13.3 and mouse chromosome 17A3.3, respectively (1, 2). Based on conserved features of the propeptides and the activation mechanism, these proteases were divided into two groups (2). Marapsin belongs to the group-1 subfamily of the human cluster, which includes testisin (PRSS21, eosinophil serine protease-1), tryptase ⑀ (PRSS22, brain-specific serine protease-4), tryptase ␥ (PRSS31, transmembrane tryptase), and EOS (PRSS33). They all contain a relatively short propeptide, which, after activation cleavage of the single chain precursor, remains attached to the protease domain via a disulfide bond. In contrast, the propeptides of group-2 subfamily members tryptase ␣, tryptase ␤1, tryptase ␤2, and tryptase ␦ are not disulfide-linked to the protease domain and are released upon activation cleavage.The 268-amino acid single-chain precursor form (zymogen) of human marapsin is converted into the active enzyme by proteolytic cleavage at the Arg 34 -Met 35 peptide bond. T...

Mutational Tail Loss Is an Evolutionary Mechanism for Liberating Marapsins and Other Type I Serine Proteases from Transmembrane Anchors

“…Mouse marapsin expressed in mammalian cells is membraneassociated but shed by phosphatidylinositol-specific phospholipase C (3), suggesting that the transmembrane peptide is swapped for a GPI anchor (12). In agreement with hydropathy analysis as well as with predictions that the human enzyme lacks a C-terminal anchor, native human marapsin is secreted from an esophageal cell line (13). The marapsin gene is expressed by a variety of human, mouse, and opossum tissues (9,10,12,13).…”

“…In agreement with hydropathy analysis as well as with predictions that the human enzyme lacks a C-terminal anchor, native human marapsin is secreted from an esophageal cell line (13). The marapsin gene is expressed by a variety of human, mouse, and opossum tissues (9,10,12,13). In humans and mice, it is especially abundant in stratified squamous epithelia of cornea, larynx, esophagus, and cervix (13,14) and is induced in wounded and psoriatic skin (13,14).…”

“…The marapsin gene is expressed by a variety of human, mouse, and opossum tissues (9,10,12,13). In humans and mice, it is especially abundant in stratified squamous epithelia of cornea, larynx, esophagus, and cervix (13,14) and is induced in wounded and psoriatic skin (13,14). These patterns of expression in combination with evidence of gene conservation in mammals encouraged speculation that marapsin serves critical functions, such as epithelial differentiation.…”

Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling

“…In contrast to major effects on the innate immune response by keratinocytes in a proinflammatory context, IL-22 and TNF-α did not synergize in the enhanced wound healing clearly induced by Th22 cells. This effect was only IL-22 dependent and reflected the induction of promigratory genes in keratinocytes by IL-22 (8,14,44,45). These data indicate a double function of IL-22 in cutaneous immunity: on the one hand, being protective and regenerative, and on the other hand, amplifying TNF-α-induced signals to contribute to a proinflammatory microenvironment during skin immune reactions.…”

Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

“…Validation of these results by quantitative reverse transcription PCR (qRT-PCR) revealed that Klk6 (22,23) and marapsin (also known as Prss27) (24) mRNAs were expressed at 10-fold higher levels in the skin from Jak1…”