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

TLDR

Programmed cell death pathways—pyroptosis, apoptosis, and necroptosis—share mechanistic overlaps and crosstalk, prompting the concept of PANoptosis, a coordinated inflammatory death that can bypass pathogen inhibition of individual pathways, though its molecular details remain largely unknown. The study investigates how bacterial and viral triggers activate PANoptosis and identifies protein interactions that form the PANoptosome complex. Macrophages were infected with influenza A virus and vesicular stomatitis virus to induce PANoptosis and characterize the resulting PANoptosome protein interactions.

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,