Fig. 6. Dsg2 ICF generation sensitizes IECs to apoptosis.
a Stimulation of death receptors (such as TNFR1 or DR4/5) results in activation of caspase-8, which cleaves Dsg2 intracellularly generating the Dsg2 ICF as well as other substrates including the Bcl-2 family member Bid-generating tBid. The presence of the Dsg2 ICF reduces Bcl-XL and Mcl1 protein levels, thereby alleviating their inhibition of tBid and allowing for MOMP and the execution of apoptosis to proceed. Following Dsg2 ICF generation, MMP9 and ADAM10 cleave Dsg2 in the extracellular domain generating the Dsg2 ECF. b) We have previously shown that this Dsg2 ECF promotes wound closure by stimulating IEC proliferation through activation of Her2/3 signaling. We propose that the Dsg2 ICF and ECF work in concert to remove damaged IECs and promote wound closure to help ensure effective resolution of inflammation. Pro-Cas8 Pro-caspase-8, Cas8 caspase-8, Cyto-c, cytochrome c