Importance of AJ and cell polarity in the regulation of Fas signaling

Fas is a transmembrane cell death receptor mostly known for its function in inducing cell death through apoptosis, but it is also recognized to be implicated in a wide range of non-death functions in various cell types and contexts. The disequilibrium between cell death and survival signals due to defective apoptosis is a key factor in tumorigenesis. Fas is found ubiquitously expressed in human tissues including many epithelia such as in the intestine. Thus, the activation of Fas signaling in this tissue should be rigorously regulated in order to maintain the balance between cell death and non-death signaling. At a cellular level, the choice of life and death, is regulated by different environmental cues including cell-cell junctions and cell polarity through the involvement of various sets of specialized macromolecules. The possible role of cell–cell contacts and cell polarity in the control of Fas signaling has been largely unexplored. Therefore, the main aim of my PhD was to investigate the role of adherens junction and cell polarity in the modulation of the FasL- induced cell death signaling in colon epithelial cells. We were able to demonstrate that both cell polarity establishment and adherens junction formation control the pro-apoptotic signaling of the death receptor Fas. We found that the Fas receptors concentrate at cell-cell junctions together with E-cadherin and that Fas-cadherin association protects cells from FasL- induced cell death. Using a proteomic approach, we identified several novel partners of Fas that interact with the C-terminal PDZ-binding site of Fas including the polarity/scaffold molecule Dlg1. We demonstrated that Dlg1 interacts directly with Fas and decrease the death- inducing complex formation upon Fas activation, therefore, providing an additional mechanism to protect against cell death. Altogether, our data show that inhibition of FasL- induced cell death by Fas-cadherin-Dlg1 complex helps to maintain epithelial homeostasis by protecting normal epithelia from apoptosis and promotes elimination of compromised non- polarized cells to avoid development of pathological conditions such as cancer development. In the second part of my PhD, I investigated the role of several partners of Fas identified in our proteomic analysis, including the E3 ubiquitin ligase LNX2. I demonstrate that LNX2 binds directly Fas, and targets activated Fas to lysosomal degradation, therefore preventing FasL- induced cell death. My results suggest that LNX2 protects colon epithelial cells against FasL- induced cell death. Interestingly, LNX2 is found overexpressed in colon cancer, which may explain how colon cancer cells evades Fas-mediated apoptosis by promoting Fas degradation following its activation.