PANoptosis: A Unique Innate Immune Inflammatory Cell Death Modality [BRIEF REVIEWS]

Abstract

Innate immunity is the first response to protect against pathogens and cellular insults. Pattern recognition receptors sense pathogen- and damage-associated molecular patterns and induce an innate immune response characterized by inflammation and programmed cell death (PCD). In-depth characterization of innate immune PCD pathways has highlighted significant cross-talk. Recent advances led to the identification of a unique inflammatory PCD modality called PANoptosis, which is regulated by multifaceted PANoptosome complexes that are assembled by integrating components from other PCD pathways. The totality of biological effects observed in PANoptosis cannot be accounted for by any other PCD pathway alone. In this review, we briefly describe mechanisms of innate immune cell death, including molecular mechanisms of PANoptosis activation and regulation. We also highlight the PANoptosomes identified to date and provide an overview of the implications of PANoptosis in disease and therapeutic targeting. Improved understanding of innate immune-mediated cell death, PANoptosis, is critical to inform the next generation of treatment strategies.

Footnotes

This work is supported by the National Institutes of Health (AI101935, AI124346, AI160179, AR056296, and CA253095 to T.-D.K.) and the American Lebanese Syrian Associated Charities (to T.-D.K.).

Abbreviations used in this article

AIM2absent in melanoma 2ASCapoptosis-associated speck-like protein containing a caspase activation and recruitment domainBAKB cell lymphoma 2–antagonist killerBAXB cell lymphoma 2–associated X proteinBCL-2B cell lymphoma 2BIDBH3-interacting domain death agonistCARDcaspase activation and recruitment domainDAMPdamage/danger-associated molecular patternFADDFas-associated death domainGSDMDgasdermin DGSDMEgasdermin EIAVinfluenza A virusIRF1IFN regulatory factor 1MHVmurine hepatitis virusMLKLmixed lineage kinase domain-like proteinMOMPmitochondrial outer membrane permeabilizationNLRnucleotide-binding oligomerization domain-like receptorNLRP3nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3PAMPpathogen-associated molecular patternPCDprogrammed cell deathPRRpattern recognition receptorRHIMRIP homotypic interaction motifRIPKreceptor-interacting protein kinaseSARS-CoV-2severe acute respiratory syndrome coronavirus 2TAKTGF-β–activated kinaseZBP1Z-DNA–binding protein 1Received July 14, 2022.Accepted August 15, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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