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 SummaryZBP1 and TAK1 regulate PAN-optosis.

Toward targeting inflammasomes: insights into their regulation and activation

“…The unveiling of ZBP1 and TAK1 as master regulators of pyroptosis, apoptosis, and necroptosis, along with the rapidly expanding evidence of communication between these pathways, has led to the concept of PANoptosis, in which a putative PANoptosome acts as a central cell death complex that can initiate all three of these pathways. 151,152 The convergence of these three programmed cell death pathways and the identification of master regulators controlling all three is intriguing and could be powerful therapeutically. Future research will be needed to determine the therapeutic potential of these master regulators and to unravel the complexities of this central PANoptotic process, including detailed exploration of the mechanisms of this multifaceted cell death.…”

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

“…Direct proteolytic cleavage of IRF3 may contribute to the reduction of type I interferon production observed in COVID19 patients [31,32]. TAB1 is part of the TAB1/2/3/TAK1 complex [70] that regulates the activity of TAK1 (TGFβ-activated kinase 1), in response to different stimuli including TGFβ, IL1, TNFα and upon viral and bacterial infection [71,72]. TAK1 can then activate the NFκB pathway or signal through the MAP kinases pathway [73,74].…”

The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

“…PANoptosis is a newly emerging concept that highlights the crosstalk and coordination that occurs between three of these pathways, that is, pyroptosis, apoptosis, and necroptosis. 46,47 Our team has been working on this concept for a decade to build on our initial findings that overlapping regulation occurs between the inflammasome/pyroptotic and apoptotic and necroptotic components. We first demonstrated the crosstalk between pyroptosis and apoptosis.…”

“…IAV infection induces multiple programmed cell death pathways concomitantly, including pyroptosis, apoptosis, and necroptosis, 28 through the process of PANoptosis in murine macrophages. 46 ZBP1 is the sensor responsible for triggering PANoptosis in response to IAV 28,70,71 ( Figure 2B). In addition to IAV, ZBP1 senses flavivirus infections, like Zika virus and West Nile virus (WNV), and induces cell death-independent antiviral effects.…”

“…ZBP1 is the sensor for influenza virus-induced NLRP3 inflammasome activation and plays a role similar to that of caspase-11 (or caspase-4/5) in LPS-induced non-canonical NLRP3 inflammasome activation. 28,46,70 Additionally, it has key roles in the initiation of IAVinduced PANoptosis. 28,46,47,54 Even though the core complex responsible for ZBP1-NLRP3 inflammasome activation has been identified, how ZBP1 sensing of influenza virus leads to NLRP3 inflammasome activation is still not fully understood.…”