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Review
. 2021 Aug 3:19:4641-4657.
doi: 10.1016/j.csbj.2021.07.038. eCollection 2021.

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

Yaqiu Wang  1 , Thirumala-Devi Kanneganti  1
Affiliations
Review

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

Yaqiu Wang et al. Comput Struct Biotechnol J. .

Abstract

Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, and they are intricately involved in both homeostasis and disease. Although the identification of key initiators, effectors and executioners in each of these three PCD pathways has historically delineated them as distinct, growing evidence has highlighted extensive crosstalk among them. These observations have led to the establishment of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. In this review, we provide a brief overview of the research history of pyroptosis, apoptosis and necroptosis. We then examine the intricate crosstalk among these PCD pathways to discuss the current evidence for PANoptosis. We also detail the molecular evidence for the assembly of the PANoptosome complex, a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and/or necroptosis. PANoptosis is now known to be critically involved in many diseases, including infection, sterile inflammation and cancer, and future discovery of novel PANoptotic components will continue to broaden our understanding of the fundamental processes of cell death and inform the development of new therapeutics.

Keywords: ASC; Apoptosis; Caspase-1; Caspase-3; Caspase-7; Caspase-8; Cell death; Gasdermin D; Gasdermin E; Inflammasome; MLKL; NLRP3; Necroptosis; PANoptosis; PANoptosome; Pyroptosis; RIPK3; ZBP1.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
Research timeline and features of programmed cell death. (A) Key milestones in the discovery and definition of apoptosis, pyroptosis, necroptosis and PANoptosis overlaid on the number of publications per year in PubMed using the search term "Cell death". (B) Morphological features of cells undergoing different forms of programmed cell death.
Fig. 2
Fig. 2
Interactome analysis of molecules in PCD pathways. A physical network of experimental and database evidence with confidence > 0.7 was retrieved from the STRING database after searching seven proteins (AIM2, PYCARD, MEFV, ZBP1, CASP1, CASP8, RIPK3) with interactor threshold 20. The interaction network was replotted by the igraph package, and historically central members of each PCD pathway are colored.
Fig. 3
Fig. 3
Model of ZBP1 PANoptosome assembly. 1) Specific trigger (e.g., IAV) is required to initiate PANoptosome formation; 2) specific sensor (e.g., ZBP1) is activated by the trigger; 3) the sensor initiates the assembly of the PANoptosome, which contains molecules required to activate downstream PCD effectors including gasdermins, CASP3/7 and MLKL; 4) PANoptosis execution by engagement of pyroptotic, apoptotic and necroptotic pathway members resulting in lytic inflammatory cell death.
Fig. 4
Fig. 4
Experimental evidence of PANoptosome formation. (A) Immunoprecipitation of RIPK3 in HEK293T cells overexpressing PANoptosome components (published data from Christgen, S., et al. Front. Cell. Infect. Microbiol., 2020). (B) Immunoprecipitation of RIPK3 in IAV-infected WT and Ripk3−/− BMDMs (left) and immunoprecipitation of CASP8 in WT cells showing the interaction among key components of the PANoptosome. (C) Immunofluorescence staining of indicated molecules in IAV-infected BMDMs showing the colocalization of principle components of the PANoptosome. BMDMs infected with IAV (PR8) at MOI = 20 for 12 h and stained with anti-ASC (2EI-7, Millipore), anti-CASP8 (1G12, Enzo) and anti-RIPK3 (B-2, Santa Cruz, pre-conjugated). Scale = 5 μm. Asterisks indicate non-specific bands.
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