SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase

Holt-Danborg, Lasse; Vodopiutz, Julia; Nonboe, Annika W.; Laffolie, Jan de; Skovbjerg, Signe; Wolters, Victorien M.; Müller, Thomas; Hetzer, Benjamin; Querfurt, Alexander; Zimmer, Klaus–Peter; Jensen, Jan K.; Entenmann, Andreas; Heinz‐Erian, Peter; Vogel, Lotte K.; Janecke, Andreas

doi:10.1093/hmg/ddy394

Cited by 26 publications

(39 citation statements)

References 46 publications

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“…Our observation that prostasin, expressed in the absence of a catalytically active matriptase in HEK293 cells, remains in its non-activated zymogen form has the implications that the proteolytic activity observed in Figures 1, 4, 5 and 6 (this study) and our previous study (13), is actually mediated by the prostasin zymogen.…”

Section: Implications Of Our Findingssupporting

confidence: 70%

“…The present study aims at elucidating the role of prostasin in the regulation of matriptase activity and is based on a previously described assay using a catalytically inactive version of matriptase (matriptase S805A) as substrate for prostasin activity (13). Our results suggest that prostasin, similar to matriptase, displays activity in its zymogen form and that the proteolytic activity of the prostasin zymogen can be inhibited by HAI-1 and HAI-2.…”

Section: Introductionmentioning

confidence: 90%

“…We have previously established a cell-based assay for detection of prostasin activity in complex samples using catalytically inactive matriptase S805A as a substrate (13). Wild-type matriptase is not suitable as a substrate as its steady state protein level depends on co-expression of HAI-1 or HAI-2 (21,22), which are both known to also inhibit prostasin.…”

Section: An Assay For Detection Of Prostasin Catalytic Activitymentioning

confidence: 99%

“…The activation of matriptase can be catalysed by another zymogen or activated matriptase molecule in a trans(auto)-activation as matriptase has specificity towards its own activation loop (17), a rare feature among serine proteases. It has also previously been shown that prostasin causes matriptase to be cleaved directly or indirectly, probably resulting in its activation (5,13,(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

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Insights into the regulation of the matriptase-prostasin proteolytic system

Holt-Danborg

Skovbjerg

Goderum

et al. 2020

Biochemical Journal

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The membrane-associated prostasin and matriptase belonging to the S1A subfamily of serine proteases, are critical for epithelial development and maintenance. The two proteases are involved in the activation of each other and are both regulated by the protease inhibitors, HAI-1 and HAI-2. The S1A subfamily of serine proteases are generally produced as inactive zymogens requiring a cleavage event to obtain activity. However, contrary to the common case, the zymogen form of matriptase exhibits proteolytic activity, which can be inhibited by HAI-1 and HAI-2, as for the activated counterpart. We provide strong evidence that also prostasin exhibits proteolytic activity in its zymogen form. Furthermore, we show that the activity of zymogen prostasin can be inhibited by HAI-1 and HAI-2. We report that zymogen prostasin is capable of activating zymogen matriptase, but unable to activate its own zymogen form. We propose the existence of an unusual enzyme-enzyme relationship consisting of proteolytically active zymogen forms of both matriptase and prostasin, kept under control by HAI-1 and HAI-2, and located at the pinnacle of an important proteolytic pathway in epithelia. Perturbed balance in this proteolytic system is likely to cause rapid and efficient activation of matriptase by the dual action of zymogen matriptase and zymogen prostasin. Previous studies suggest that the zymogen form of matriptase performs the normal proteolytic functions of the protease, whereas excess matriptase activation likely causes carcinogenesis. HAI-1 and HAI-2 are thus important for the prevention of matriptase activation whether catalysed by zymogen/activated prostasin (this study) or zymogen/activated matriptase (previous studies).

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Section: Implications Of Our Findingssupporting

confidence: 70%

Section: Introductionmentioning

confidence: 90%

Section: An Assay For Detection Of Prostasin Catalytic Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insights into the regulation of the matriptase-prostasin proteolytic system

Holt-Danborg

Skovbjerg

Goderum

et al. 2020

Biochemical Journal

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“…The presence of SPINT2 is found throughout the gastrointestinal tract of humans and mice [ 52 ]. Matriptase, prostasin, SPINT1, and SPINT2 are coexpressed in most developing and adult mammalian epithelia.…”

Section: Etiology and Pathogenesismentioning

confidence: 99%

Tufting Enteropathy: A Review of Clinical and Histological Presentation, Etiology, Management, and Outcome

Cai

Chen

et al. 2020

Gastroenterology Research and Practice

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Congenital tufting enteropathy (CTE), also named intestinal epithelial dysplasia, is a rare, autosomal recessive enteropathy with persistent and life-threatening intractable diarrhea early in life. Intractable diarrhea is present independent of breast or formula feeding. Most CTE patients require total parenteral nutrition (TPN), and in severe cases, small bowel transplantation is needed. In the last decade, we have seen remarkable progress in certain aspects, such as the pathogenesis and diagnostic methods of the disease. Rapidly developing molecular analysis techniques have improved the diagnostic methods for CTE and reduced invasive and expensive procedures. Mutations in the gene encoding human epithelial cell adhesion molecule (EpCAM) were identified in the typical form of CTE, which usually exhibits isolated refractory diarrhea. Moreover, the syndromic form of CTE features anal and choanal atresias as well as ophthalmologic signs, which are associated with mutations in the gene encoding Serine Peptidase Inhibitor Kunitz Type 2 (SPINT2). This article reviews CTE disease based on its clinical and histological presentation, etiology and pathogenesis, and management and outcome.

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Expansion of the ophthalmic phenotype of SPINT2‐related syndromic congenital sodium diarrhea

Ernst

Hiasat

Alabek

et al. 2021

American J of Med Genetics Pt A

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A 5‐year‐old girl presented with treatment‐refractory dry eye and recurrent episodes of eye pain. She had been previously diagnosed with syndromic congenital sodium diarrhea (SCSD) caused by a pathogenic variant in SPINT2. Her local pediatric ophthalmologist had made the diagnosis of severe dry eye with corneal erosions, based on which, we arranged an eye exam under anesthesia (EUA) and punctal plug placement. Anterior segment optical coherence tomography (OCT) and corneal photographs were taken during the procedure. There are reports describing similar ophthalmic findings in this syndrome. However, to the best of our knowledge, this is the first case report to document OCT imaging and corneal photographs in a patient with SCSD, which we feel expands the ophthalmic phenotype of this rare genetic disorder.

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SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase

Cited by 26 publications

References 46 publications

Insights into the regulation of the matriptase-prostasin proteolytic system

Insights into the regulation of the matriptase-prostasin proteolytic system

Tufting Enteropathy: A Review of Clinical and Histological Presentation, Etiology, Management, and Outcome

Expansion of the ophthalmic phenotype of SPINT2‐related syndromic congenital sodium diarrhea

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