PANoptosis

PANoptosis is a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through multiprotein PANoptosome complexes.^[1][2] The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer.^{[1][3][4][5][6][7][8][9][10][11][12][13][14][15][16]} Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRC5- and NLRP12-PANoptosomes, have been characterized so far.^{[1][17][18][19][20][21][22][23]}

Emerging genetic, molecular, and biochemical studies have identified extensive crosstalk among the molecular components across various cell death pathways in response to a variety of pathogens and innate immune triggers.^[3][4] Historically, inflammatory caspase-mediated pyroptosis  and RIPK-driven necroptosis were described as two major inflammatory cell death pathways. While the PANoptosis pathway has some molecular components in common with pyroptosis and necroptosis, as well as with the non-lytic apoptosis pathway, these mechanisms are separate processes that are associated with distinct triggers, protein complexes, and execution pathways.^[2] Inflammasome-dependent pyroptosis involves inflammatory caspases, including caspase-1 and caspase-11 in mice, and caspases-1, -4, and -5 in humans, and is executed by gasdermin D.^{[24][25][26][27][28][29][30]} In contrast, necroptosis occurs via RIPK1/3-mediated MLKL activation, which is downstream of caspase-8 inhibition.^{[31][32][33][34]} On the other hand, PANoptosis is [TDK1] driven by caspases and RIPKs and is executed by gasdermins, MLKL, NINJ1, and potentially other yet to be identified molecules cleaved by caspases.^{[35][36][37][38][39][40][19][21]} Moreover, caspase-8 is essential for cell death in PANoptosis^[41][42] but needs to be inactivated or inhibited to induce necroptosis.^[43][44]

Summary of the different morphologies, mechanisms and outcomes of apoptosis, pyroptosis, necroptosis, and PANoptosis