Figure 3.

ZBP1 activation triggers the assembly of signaling complexes to be involved in the induction of necroptosis and inflammatory responses. Upon microbial infection or cellular stress response, activation of ZBP1 leads to the recruitment of receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and caspase-8 to form cell death-signaling complexes. This ZBP1-RPK3-Caspase 8 scaffold further promotes the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3). PYCARD and Caspase-1 contain the inflammasome complex, which leads to cleavage of pro-IL-1β and IL-18 into an active form, which results in inducing inflammatory responses. Activation of ZBP1 also stimulates RIPK1-driven inflammatory responses via NF-κB and MAPKs signaling (JNKs, p38 and ERK1/2) activation. Dotted lines also represent TLR2/3/4-induced inflammatory responses through RIPK3-MLKL, which induces necrosome complex formation under caspase-8 inhibition.