A survival mechanism controlled by cadherins and Dlg1 polarity complex inhibits Fas cell death receptor signaling

A fine regulation of epithelia cell death is required to maintain tissue integrity and homeostasis. At a cellular level, this life and death decision is controlled by environmental stimuli including death receptors activation. Here, we show that establishment of cell polarity and AJ formation control the pro-apoptotic signaling emanating from the death receptor Fas. We demonstrate that in colon epithelia Fas concentrates at cell-cell junctions together with the E-cadherin, which protects cells from FasL-induced cell death. The Fas-cadherin association requires the C terminal PDZ binding site of Fas and, using a proteomic approach, we showed that this domain allows the association with the polarity molecule Dlg1. We proved that the interaction of Fas with this scaffold molecule participate to this cell death protection. Therefore inhibition of FasL-induced cell death by Fas-cadherin-Dlg1 complex is a double-edged sword mechanism that helps to maintain epithelial homeostasis by (i) protecting normal polarized epithelia from apoptosis (ii) promoting the elimination of compromised non-polarized cells.