AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence

Abstract

Summary Inflammasomes are important sentinels of innate immune defense, sensing pathogens and inducing cell death in infected cells 1 . There are several inflammasome sensors that each detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) 1 . In contrast to this one PAMP/DAMP to one sensor specificity, during infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which could contemporaneously engage multiple inflammasome sensors 2 – 5 . Here we discovered that AIM2 regulated the innate immune sensors Pyrin and ZBP1 to drive inflammatory signaling and inflammatory cell death, PANoptosis, and provide host protection during infections with herpes simplex virus 1 (HSV1) and Francisella novicida . We also observed that AIM2, Pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD that drove inflammatory cell death. Collectively, our findings define a previously unknown regulatory connection and molecular interaction among AIM2, Pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that involves multiple inflammasome sensors and cell death regulators. These results represent a new paradigm in understanding the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and Pyrin-mediated diseases.

Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression

“…IL-1β is controlled through inflammasome-mediated proteolytic maturation of pro-IL-1β. Inflammasomes are multiprotein complexes consisting of caspase-1, ASC, and cytoplasmic pathogen recognition receptors (PRRs) such as nucleotide-binding oligomerization domain (NOD)-like receptor family proteins (NLRPs) and absent in melanoma 2 (AIM2)-like receptors (ALRs) [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Mitochondrial dysfunction promotes alternative gasdermin D-mediated inflammatory cell death and susceptibility to infection

“…6C). Because the PANoptosome involves the coordinated efforts of AIM2, ZBP1, and caspase-8 109 , these data argue that PANoptosis is not active in Lrrk2 G2019S macrophages following inflammasome activation.…”

“…PANoptosis is a newly described type of cell death in which apoptosis, pyroptosis, and necroptosis pathways are all engaged in parallel following complex inflammasome triggers like HSV or Francisella novicida infection [109][110][111] . PANoptosis is driven by formation of the PANoptosome, a complex that coordinates the efforts of AIM2, ZBP1, and pyrin to promote caspase-1-, caspase-3,7,8-and MLKL-dependent inflammatory cell death 109 . Necroptosis is another form of inflammatory programmed cell death in which the RHIM domain containing proteins RIPK1/RIPK3 activate the pore-forming protein MLKL downstream of a variety of stimuli including mtDNA release 112 , ROS and cytokine signaling 113,114 , PAMPs, and caspase inhibition.…”

“…6A). PANoptosis is a newly described type of cell death in which apoptosis, pyroptosis, and necroptosis pathways are all engaged in parallel following complex inflammasome triggers like HSV or Francisella novicida infection [109][110][111] . PANoptosis is driven by formation of the PANoptosome, a complex that coordinates the efforts of AIM2, ZBP1, and pyrin to promote caspase-1-, caspase-3,7,8-and MLKL-dependent inflammatory cell death 109 .…”

Integrated stress response restricts macrophage necroptosis

“…More recently, the extensive crosstalk between cell death pathways has led to the concept of PANoptosis, which is defined as an inflammatory programmed cell death pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these pathways alone. The PANoptosome provides a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and necroptosis (Lamkanfi et al, 2008;Malireddi et al, 2010Malireddi et al, , 2018Malireddi et al, , 2019Malireddi et al, , 2020aMalireddi et al, , 2020bGurung et al, 2014Gurung et al, , 2016Lukens et al, 2014;Kuriakose et al, 2016;Banoth et al, 2020;Christgen et al, 2020;Karki et al, 2020aKarki et al, , 2020bKarki et al, , 2021Kesavardhana et al, 2020b;Lee et al, 2021). Given the inflammatory consequences of cell death, cells possess multiple negative regulatory pathways that restrict excessive inflammation.…”