It's All in the PAN: Crosstalk, Plasticity, Redundancies, Switches, and Interconnectedness Encompassed by PANoptosis Underlying the Totality of Cell Death-Associated Biological Effects

Abstract

The innate immune system provides the first line of defense against cellular perturbations. Innate immune activation elicits inflammatory programmed cell death in response to microbial infections or alterations in cellular homeostasis. Among the most well-characterized programmed cell death pathways are pyroptosis, apoptosis, and necroptosis. While these pathways have historically been defined as segregated and independent processes, mounting evidence shows significant crosstalk among them. These molecular interactions have been described as 'crosstalk', 'plasticity', 'redundancies', 'molecular switches', and more. Here, we discuss the key components of cell death pathways and note several examples of crosstalk. We then explain how the diverse descriptions of crosstalk throughout the literature can be interpreted through the lens of an integrated inflammatory cell death concept, PANoptosis. The totality of biological effects in PANoptosis cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. We also discuss PANoptosomes, which are multifaceted macromolecular complexes that regulate PANoptosis. We consider the evidence for PANoptosis, which has been mechanistically characterized during influenza A virus, herpes simplex virus 1, Francisella novicida, and Yersinia infections, as well as in response to altered cellular homeostasis, in inflammatory diseases, and in cancers. We further discuss the role of IRF1 as an upstream regulator of PANoptosis and conclude by reexamining historical studies which lend credence to the PANoptosis concept. Cell death has been shown to play a critical role in infections, inflammatory diseases, neurodegenerative diseases, cancers, and more; therefore, having a holistic understanding of cell death is important for identifying new therapeutic strategies.

Keywords: AIM2; ASC; IRF1; MLKL; NLR; NLRP3; PANoptosis; PANoptosome; Pyrin; RIPK1; RIPK3; ZBP1; apoptosis; caspase; caspase-1; caspase-3; caspase-7; caspase-8; crosstalk; infection; inflammasome; inflammation; inflammatory cell death; innate immunity; necroptosis; plasticity; pyroptosis; redundancy.

Figure 1

PANoptosis and PANoptosome formation. Upon exposure to cellular insults, such as microbial infection or altered cellular homeostasis, sensors can detect the perturbation and activate PANoptosis. Prototypical examples of PANoptosis are depicted here. Sensor activation can lead to the formation of a multiprotein complex, the PANoptosome. PANoptosomes have the potential to bring together diverse components from previously segregated cell death pathways. These may be dynamic complexes, and their protein composition may vary in trigger- and time-dependent manners. Potential PANoptosome components putatively include inflammasome sensors, such as nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), absent in melanoma 2 (AIM2), Pyrin, Z-DNA-binding protein 1 (ZBP1), or others; apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC); caspase-1 (CASP1); receptor-interacting serine/threonine protein kinase 3 (RIPK3); RIPK1; caspase-8 (CASP8); Fas-associated protein with death domain (FADD); and/or caspase-6 (CASP6). PANoptosis involves membrane pore formation for the execution of cell death to release cytokines, such as IL-1β and IL-18, and DAMPs. Figure created with https://biorender.com/ (accessed on 17 March 2022).