ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis)

Abstract

Cell death is central to development, organismal homeostasis, and immune responses. The cell death field has experienced tremendous progress by delineating the molecular programs specific to each of the apoptotic and inflammatory cell death pathways. Moreover, the discovery of the inflammasomes and pyroptosis and necroptosis pathway regulators have provided the genetic basis for the programmed inflammatory cell death pathways. Earlier research highlighted the unique regulation of each of these pathways, but emerging studies discovered co-regulation and crosstalk between these seemingly different cell death complexes. The progress in this area has led to an idea that master regulators play central roles in orchestrating multiple cell death pathways. Here, we provide a brief review of the master regulators, the innate immune sensor ZBP1 and the essential cell survival kinase TAK1, that play vital roles in the regulation of RIPK1/RIPK3-FADD-caspase-8 cell death complex assembly and its versatility in executing Pyroptosis, Apoptosis, and Necroptosis, which we dubbed here as PAN-optosis. Furthermore, we discuss the implications and therapeutic potential of targeting these master regulators in health and disease.

One sentence summary: ZBP1 and TAK1 regulate PAN-optosis.

Keywords: MLKL; TLR priming; caspase-1; gasdermin D; infection; inflammasome; inflammation; innate immunity.

Figure 1

Activation of ZBP1 triggers assembly of signaling complexes to engage PAN-optosis. Z-DNA binding protein 1 (ZBP1) is an innate immune receptor that senses nucleic acids and activates PAN-optosis and inflammation. ZBP1 activation leads to its interaction with receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and recruitment of caspase-8 (CASP8) to form cell death signaling scaffolds. This ZBP1-RIPK3-CASP8 complex engages nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-dependent pyroptosis, CASP8-mediated apoptosis, and RIPK3-mixed lineage kinase domain-like pseudokinase (MLKL)–driven necroptosis. ZBP1 also induces RIPK1-driven NF-κB activation and inflammation in response to influenza infection. Red boxes within proteins represent the RIP homotypic interaction motif (RHIM) domain. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; C, C-terminus; CASP1, caspase-1; GSDMD, gasdermin D; N, N-terminus.

Figure 2

TAK1 acts as a master switch for PAN-optosis quiescence. Genetic deletion or microbial or pharmacological inactivation of transforming growth factor beta-activated kinase 1 (TAK1) function triggers receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent assembly of PAN-optotic cell death complexes. RIPK1 in association with FS7-associated cell surface antigen (Fas)-associated death domain (FADD) and caspase-8 (CASP8) triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-dependent and CASP8-mediated cleavage of gasdermin D (GSDMD) and the execution of pyroptosis. This complex also engages CASP8-mediated apoptosis, and inhibition of CASP8 activity promotes RIPK3-mixed lineage kinase domain-like pseudokinase (MLKL)–dependent necroptosis. Red boxes within proteins represent the RIP homotypic interaction motif (RHIM) domain. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; C, C-terminus; CASP1, caspase-1; cIAP, cellular inhibitor of apoptosis protein; LUBAC, linear ubiquitin chain assembly complex; N, N-terminus; NEMO, NF-κB essential modulator; TAB, TAK1 binding protein.