Bacteroides fragilis Toxin Induces Extracellular Domain Cleavage of HER2 in Intestinal Epithelial Cells.

Enterotoxigenic Bacteroides fragilis (ETBF) secretes Bacteroides fragilis toxin (BFT), a metalloprotease that disrupts intestinal epithelial integrity and activates pro-inflammatory signaling. Although E-cadherin cleavage is a well-established response to BFT, the involvement of other membrane receptors in BFT-induced signaling remains poorly defined. In this study, we examined whether HER2 undergoes proteolytic processing following BFT exposure and whether HER2 contributes to BFT-induced ERK activation. In HT29/c1 and MCF-7 epithelial cells, BFT induced the loss of full-length 185 kDa HER2 and the generation of a membrane-tethered ~95 kDa fragment. This truncated HER2 underwent γ-secretase-dependent intramembrane processing and subsequent proteasomal degradation. Knockdown of MMP-7 or ADAM10 did not prevent HER2 cleavage, indicating that neither protease is required for this process. In addition, BFT-induced ERK phosphorylation was observed in HER2-expressing cells but was abolished in HER2-deficient HT29/c1 clones, whereas E-cadherin cleavage and IL-8 secretion remained detectable. These findings identify HER2 as a previously unrecognized target of BFT-induced proteolytic remodeling and support a contribution of HER2 to BFT-induced ERK activation.