Both the anti- and pro-apoptotic functions of villin regulate cell turnover and intestinal homeostasis

Abstract

In the small intestine, epithelial cells are derived from stem cells in the crypts, migrate up the villus as they differentiate and are ultimately shed from the villus tips. This process of proliferation and shedding is tightly regulated to maintain the intestinal architecture and tissue homeostasis. Apoptosis regulates both the number of stem cells in the crypts as well as the sloughing of cells from the villus tips. Previously, we have shown that villin, an epithelial cell-specific actin-binding protein functions as an anti-apoptotic protein in the gastrointestinal epithelium. The expression of villin is highest in the apoptosis-resistant villus cells and lowest in the apoptosis-sensitive crypts. In this study we report that villin is cleaved in the intestinal mucosa to generate a pro-apoptotic fragment that is spatially restricted to the villus tips. This cleaved villin fragment severs actin in an unregulated fashion to initiate the extrusion and subsequent apoptosis of effete cells from the villus tips. Using villin knockout mice, we validate the physiological role of villin in apoptosis and cell extrusion from the gastrointestinal epithelium. Our study also highlights the potential role of villin’s pro-apoptotic function in the pathogenesis of inflammatory bowel disease, ischemia-reperfusion injury, enteroinvasive bacterial and parasitic infections.

A Detailed Study of Rainbow Trout (Onchorhynchus mykiss) Intestine Revealed That Digestive and Absorptive Functions Are Not Linearly Distributed along Its Length

“…Slender cells, with a strong eosinophilic cytoplasm, were observed only in the distal intestine, on the apical part of the complex folds and in the pyloric caeca. These features correspond to the early apoptotic stages in which dying cells assume the typical funnel-like structure with crescent nuclei and display a strongly acidophilic cytoplasm due to chromatin condensation [34].…”

Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine

“…S4 D , Right ) d after 56 Fe relative to control and γ-rays, suggesting increased cell–ECM attachment promoting reduced cellular mobility. Coordinated cell migration along the crypt–villus axis also requires timely cell extrusion in the villus tip area, and proapoptotic NH 2 -terminal villin has been reported to play key roles in cell shedding ( 18 ). Immunohistochemistry for NH 2 -terminal villin showed reduced expression in the villus tip area at 7 ( Fig.…”

“…Integrins have been reported to modulate the DNA damage response, and activation of β1-integrin decreased DNA damage-induced apoptosis ( 16 ). Migrating IECs are shed at the villus tip via apoptosis, and the actin-binding protein villin, through its differential cleavage and interaction with actin, has been shown to regulate cell turnover in the villi ( 18 ). While heavy-ion radiation is capable of inducing long-lasting cellular stress and DNA damage ( 4 , 19 ), its effects on key cellular processes involved in IEC migration and pathological implications of their dysregulation on GI tissue are poorly defined.…”

Forecast of actin-binding proteins as the oncotarget in osteosarcoma – a review of mechanism, diagnosis and therapy

“… 18 , 101 , 102 However, two aspects of villin’s regulation in the apoptosis of gastrointestinal epithelium have been reported, which include maintaining morphology and homeostasis. 103 These processes may also be responsible for chemoresistance in OS therapy, which has been proved in ovarian and head-and-neck cancers. 104 , 105 Meanwhile, in breast cancer, it has been indicated that fascin has the capability to enhance the resistance of chemotherapy and makes for a poor prognosis in patients.…”