Figure 6.

Proposed model. In WT keratinocytes, HOIP forms a constitutive interaction with caspase-1 and mediates the linear ubiquitination of the CARD pro-domain. Upon engagement of apoptosis, caspase-1 and caspase-8 cleave HOIP at Asp-348 and Asp-387, limiting the ability of LUBAC to ubiquitinate substrates. This results in attenuated NF-κB–dependent gene expression and enhanced cell death. Activation of apoptosis in the absence of LUBAC leads to enhanced caspase-1, -3, and -8 activity, which promotes dermatitis in vivo.