The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis)

Abstract

Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death-pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.

Therapeutic modulation of inflammasome pathways

“…55 TAK1 inhibition and a host of additional microbial pathogens also induce NLRP3 inflammasome-mediated pyroptosis concomitant with induction of necroptosis and extrinsic apoptosis in the targeted cell population, a process that was recently coined as PANoptosis. [56][57][58][59] Moreover, gain-of-function mutations in NLRP3 cause autosomal dominantly inherited autoinflammatory diseases that are collectively named Cryopyrin-Associated Periodic Syndrome (CAPS), and which comprise-in increasing order of clinical severity-familial F I G U R E 1 Overview of different inflammasome complexes: (From left to right) Engagement of different TLR receptors leads to activation of IKKs, which in turn results in activation of NF-κB signaling. Consequently, NF-κB upregulates different pro-inflammatory cytokines such as TNF, IL-6, and pro-IL-1β.…”

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

“…Most recently, we found that this concept can be applied to various pathogens including IAV, vesicular stomatitis virus (VSV), Listeria monocytogenes, and Salmonella enterica serovar Typhimurium, and we characterized a single cell death complex, the PANoptosome, that initiates this process. 47,55 While our initial work found that NLRP3 is a key molecule in this complex, 53,54 our discovery of PANoptosis in the context of pathogens that are recognized by other inflammasome sensors suggests that these molecules may also play a role in PANoptosome formation. 47,55 PANoptosis is also observed during development.…”

“…47,55 While our initial work found that NLRP3 is a key molecule in this complex, 53,54 our discovery of PANoptosis in the context of pathogens that are recognized by other inflammasome sensors suggests that these molecules may also play a role in PANoptosome formation. 47,55 PANoptosis is also observed during development. Loss of the caspase activity of caspase-8 leads to the activation of PANoptosis, which results in large amounts of cell death and inflammation in the intestine and embryonic lethality.…”

“…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.…”

ZBP1: A STARGᐰTE to decode the biology of Z-nucleic acids in disease

“…Thus, ZBP1 activation is cell intrinsic under sterile conditions, and endogenous nucleic acids may potentially be the ligands engaging its activation. Other recent studies also have shown that the Zα domains of ZBP1 are critical for triggering skin and bowel inflammation, the perinatal lethality of Ripk1 mRHIM mice, and IAV-induced PANoptosis via the assembly of a PANoptosome, suggesting a role for Z-NA sensing in regulating physiological functions (Table 1; Christgen et al, 2020;Jiao et al, 2020;Kesavardhana et al, 2020;Samir et al, 2020;Wang et al, 2020;Zhang et al, 2020). Under sterile conditions, double-stranded RNAs (dsRNAs) from endogenous retrovirus (ERV) elements bind ZBP1 and are implicated in its activation (Jiao et al, 2020;Wang et al, 2020).…”