Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity

Abstract

Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-bound serine protease inhibitor expressed in epithelial tissues. Mutant mouse models revealed that HAI-1/SPINT1 is essential for placental labyrinth formation and is critically involved in regulating epidermal keratinization through interaction with its cognate cell surface protease, matriptase. HAI-1/SPINT1 is abundantly expressed in both human and mouse intestinal epithelium; therefore, we analyzed its role in intestinal function using mice with intestinal epithelial cell-specific deletion of Spint1 generated by interbreeding mice carrying Spint1 LoxP homozygous alleles with transgenic mice carrying the Cre recombinase gene controlled by the intestine-specific Villin promoter. Although the resulting mice had normal development and appearance, crypts in the proximal aspect of the colon, including the cecum, exhibited histologic abnormalities and increased apoptosis and epithelial cell turnover accompanied by increased intestinal permeability. Distended endoplasmic reticula were observed ultrastructurally in some crypt epithelial cells, indicative of endoplasmic reticular stress. To study the role of HAI-1/SPINT1 in mucosal injury, we induced colitis by adding dextran sodium sulfate to the drinking water. After dextran sodium sulfate treatment, intestine-specific HAI-1/SPINT1-deficient mice had more severe symptoms and a significantly lower survival rate relative to control mice. These results suggest that HAI-1/SPINT1 plays an important role in maintaining colonic epithelium integrity.

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

“…−/− placentas display phenotypic hallmarks of Spint1 deficiency Spint1 encodes a cell membrane-associated Kunitz type 1 serine protease inhibitor (Shimomura et al, 1997) that is expressed in several epithelial cells and tissues, including the placenta, kidney and intestine (Kataoka et al, 2000;Yamauchi et al, 2004;Oberst et al, 2005;Szabo et al, 2007;Kawaguchi et al, 2011). Similar to Grhl2 −/− placentas, chorionic trophoblasts of Spint1 −/− placentas fail to establish a labyrinth, fetal vascularization is absent, and the trophoblast layer appears to be compact (Tanaka et al, 2005;Fan et al, 2007;Szabo et al, 2007).…”

Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Suppressor of Intestinal Tumorigenesis

“…Matriptase, encoded by the ST14 gene, belongs to the type II transmembrane serine protease superfamily and is expressed on the epithelial cell surface of most epithelial tissues (6). Moreover, recent studies indicate that its cognate cell surface inhibitor, hepatocyte growth factor activator inhibitor (HAI), also has crucial roles in epithelial functions (7)(8)(9)(10).…”

“…Unlike HAI-2/ SPINT2, HAI-1/SPINT1 also has an N-terminal cysteine-rich domain and a low-density lipoprotein receptor type A-like domain (11). HAI-1/SPINT1 is expressed in most epithelial cells, with significant expression in enterocytes (8,12). HAI-1/ SPINT1 was initially discovered as an endogenous inhibitor of HGF activator, a serum-derived serine protease (13), but its membrane association may also allow it to regulate cell surface serine proteases.…”

“…In fact, HAI-1/SPINT1 has essential functions in placental trophoblasts, epidermal keratinocytes, and hair follicle epithelium (7,21). Recently, we reported that conditional deletion of the Spint1 gene in intestinal epithelial cells results in enhanced intestinal permeability and susceptibility to dextran sulfate sodium (DSS)-induced colitis (8). As intestinal epithelial integrity has an important protective role against mucosal inflammation and neoplastic progression (1,2,22), HAI-1/SPINT1 may have a significant role in intestinal tumorigenesis.…”

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

“…14e20 By using Spint1 mutant mouse models, we previously reported that HAI-1 is critically required in the development of the placental labyrinth 21 and normal keratinization of the skin, 22 and it may also contribute to intestinal epithelial barrier function. 23 In the absence of HAI-1, epidermis showed hyperkeratosis and decreased barrier function in mice. 22 Moreover, hair cuticle formation was severely impaired.…”