Identification of the PANoptosome: A Molecular Platform Triggering Pyroptosis, Apoptosis, and Necroptosis (PANoptosis)

Abstract

Programmed cell death plays crucial roles in organismal development and host defense. Recent studies have highlighted mechanistic overlaps and extensive, multifaceted crosstalk between pyroptosis, apoptosis, and necroptosis, three programmed cell death pathways traditionally considered autonomous. The growing body of evidence, in conjunction with the identification of molecules controlling the concomitant activation of all three pathways by pathological triggers, has led to the development of the concept of PANoptosis. During PANoptosis, inflammatory cell death occurs through the collective activation of pyroptosis, apoptosis, and necroptosis, which can circumvent pathogen-mediated inhibition of individual death pathways. Many of the molecular details of this emerging pathway are unclear. Here, we describe the activation of PANoptosis by bacterial and viral triggers and report protein interactions that reveal the formation of a PANoptosome complex. Infection of macrophages with influenza A virus, vesicular stomatitis virus, Listeria monocytogenes, or Salmonella enterica serovar Typhimurium resulted in robust cell death and the hallmarks of PANoptosis activation. Combined deletion of the PANoptotic components caspase-1 (CASP1), CASP11, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and CASP8 largely protected macrophages from cell death induced by these pathogens, while deletion of individual components provided reduced or no protection. Further, molecules from the pyroptotic, apoptotic, and necroptotic cell death pathways interacted to form a single molecular complex that we have termed the PANoptosome. Overall, our study identifies pathogens capable of activating PANoptosis and the formation of a PANoptosome complex.

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.…”

Molecular mechanisms activating the NAIP‐NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer

“…The recruitment of multiple caspases diversifies the signaling and functional repertoire of the NLRC4 inflammasome, providing more ways to orchestrate host responses. Indeed, in response to infection by S Typhimurium, NLRC4 might activate multiple caspase‐dependent and caspase‐independent cell death pathways, including pyroptosis, apoptosis, and necroptosis, collectively known as PANoptosis 93 …”

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.…”