Figure 4.

A working model for induction of cardiomyocyte necroptosis by Cops8 deficiency. Loss of function of Cops8/CSN is expected to suppress the CRLs shown in green font, which in turn disrupts the respective ubiquitination events and thereby blocks NFκB-mediated survival signaling and inhibits the apoptotic pathway via increasing BCL2 and hindering the activation of caspase-8 (Casp8), steering the death receptor-triggered pathway to the RIPK1–RIPK3-mediated necroptosis. The pathways in the shaded zone are likely involved but not directly examined in Cops8-deficient mice. It is hypothesized that TFNα comes from autocrinal or paracrinal routes from the myocardium with cardiomyocyte-restricted Cops8 knockout (Cops8-CKO). The interrogations that have been completed are marked with bold black font. Dotted line denotes a potential link that has not been tested yet. Nec-1, necrostatin-1; p-IκBα, phosphorylated IκBα; Psm, proteasomal degradation; RIPK3-KO, global knockout of RIPK3; ROS, reactive oxygen species [adopted from Xiao et al. (2020)].