Abstract
Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death—pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.
Highlights
Programmed cell death (PCD) is an evolutionarily conserved process that plays central roles in maintaining organismal homeostasis
The recent progress in our understanding of the extensive crosstalk between different cell death and signaling cascades unequivocally establishes the existence of multifaceted signaling platforms
The PANoptosome appears to have evolved to efficiently utilize diverse modes of cellular communication that include domainbased scaffolds and enzyme-based catalytic modifications to engage PANoptosis. Using these diverse cellular mechanisms might be an important way in which the PANoptosome incorporates fundamentally different modes of cell death to orchestrate homeostasis during developmental programs while driving a robust inflammatory form of cell death for immune-mediated protection against microbial infections
Summary
Programmed cell death (PCD) is an evolutionarily conserved process that plays central roles in maintaining organismal homeostasis.
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