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Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM
Roman Szabo1, Makiko Kawaguchi2, Hiroaki Kataoka2
1Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Congenital tufting enteropathy (CTE) is a life-threatening intestinal disorder resulting from loss-of-function mutations in EPCAM and SPINT2. Mice deficient in Spint2, encoding the protease inhibitor HAI-2, develop CTE-like intestinal failure associated with a progressive loss of the EpCAM protein, which is caused by unchecked activity of the serine protease matriptase (ST14). Here, we show that loss of HAI-2 leads to increased proteolytic processing of EpCAM. Elimination of the reported matriptase cleavage site strongly suppressed proteolytic processing of EpCAM in vitro and in vivo. Unexpectedly, expression of cleavage-resistant EpCAM failed to prevent intestinal failure and postnatal lethality in Spint2-deficient mice. In addition, genetic inactivation of intestinal matriptase (St14) counteracted the effect of Spint2 deficiency in mice expressing cleavage-resistant EpCAM, indicating that matriptase does not drive intestinal dysfunction by excessive proteolysis of EpCAM. Interestingly, mice expressing cleavage-resistant EpCAM developed late-onset intestinal defects and exhibited a shortened lifespan even in the presence of HAI-2, suggesting that EpCAM cleavage is indispensable for EpCAM function. Our findings provide new insights into the role of EpCAM and the etiology of the enteropathies driven by Spint2 deficiency.
Insights
Loss of HAI-2 causes congenital tufting enteropathy (CTE) by increasing EpCAM protein cleavage. However, blocking this cleavage does not prevent intestinal failure, suggesting EpCAM cleavage is essential for its function.
Area of Science:
- Gastroenterology
- Molecular Biology
- Genetics
Background:
- Congenital tufting enteropathy (CTE) is a severe intestinal disorder linked to mutations in EPCAM and SPINT2.
- SPINT2 deficiency leads to intestinal failure due to EpCAM loss, driven by matriptase activity.
Purpose of the Study:
- To investigate the role of EpCAM proteolytic processing in SPINT2-deficient mice and its contribution to CTE.
- To determine if blocking EpCAM cleavage can prevent intestinal failure in CTE models.
Main Methods:
- Utilized Spint2-deficient mouse models with modified EpCAM (cleavage-resistant).
- Assessed the impact of EpCAM cleavage site mutations on protein processing in vitro and in vivo.
- Investigated the effect of matriptase (St14) inactivation on intestinal function in Spint2-deficient and EpCAM mutant mice.
Main Results:
- Loss of HAI-2 (SPINT2) increased EpCAM proteolytic processing, mediated by matriptase.
- Eliminating the matriptase cleavage site reduced EpCAM processing but did not rescue intestinal failure in Spint2-deficient mice.
- Cleavage-resistant EpCAM expression led to late-onset intestinal defects and reduced lifespan, even with functional HAI-2.
Conclusions:
- Matriptase-mediated EpCAM cleavage is not the primary driver of intestinal failure in Spint2 deficiency.
- EpCAM cleavage is essential for normal EpCAM function and intestinal homeostasis.
- Findings offer new insights into CTE pathogenesis and EpCAM's role in intestinal health.
