Study details the role of PANoptosome in activating innate immune response

Immunologists from St. Jude Children’s Research Hospital discovered how immune sensors in infected cells organize and initiate a multi-faceted innate immune response to infections with living bacteria and viruses. The research was published on September 1^st, 2021, in the Nature journal.

Corresponding author Thirumala-Devi Kanneganti, PhD, of the St. Jude Department of Immunology, identified how immune sensors in infected cells organize and launch a multi-faceted innate immune response to infections with live viruses and bacteria. Image Credit: St. Jude Children’s Research Hospital.

The observations provide new insights into the functional and regulatory role that cell death complexes and inflammasome sensors accomplish in infections. The research also outlines novel therapeutic targets for the treatment of diseases like inflammatory autoimmune disorders and cancer that are linked with abnormal inflammasome sensor activation.

Inflammasomes are protein complexes that develop in infected cells or cells that perceive damage. The complexes comprise sensors that identify various bacteria viruses, and other pathogens or danger signals. Inflammasomes trigger inflammatory signaling.

These signals stimulate inflammatory cell death pathways and annihilate the infection along with contributing to pathological inflammation. Earlier research concentrated on inflammasomes functioning alone.

This new work builds on our quest to identify inflammasome regulation. Our study highlights how inflammasomes and multiple cell death components can and do work together in a mega-protein complex called the PANoptosome to activate the innate immune response and unleash PANoptosis.”

Thirumala-Devi Kanneganti, PhD, Study Corresponding Author, Department of Immunology, St. Jude Children’s Research Hospital

The Kanneganti lab demonstrated that regulatory and molecular interactions between three inflammasome sensors, in unison with cell death proteins, urge the formation of a mega-cell death complex named a PANoptosome. Instead of regulating a single type of inflammatory programmed cell death, PANoptosomes control three—apoptosis, pyroptosis, and necroptosis, indicated as PANoptosis.

Investigators also identified that the AIM2 inflammasome sensor operated as a master regulator of PANoptosome assembly in response to infections with Francisella novicida bacterium and the herpes simplex virus 1. AIM2 also proved vital for enabling mice to endure infections.

The findings address a central question in the fields of innate immunity, cell death, and inflammasome biology.”

Thirumala-Devi Kanneganti, PhD, Study Corresponding Author, Department of Immunology, St. Jude Children’s Research Hospital

From inflammasomes to PANoptosomes

The observations based on an earlier study from Kanneganti’s lab are a pioneer in the research area. Kanneganti pinpointed one of the first inflammasome sensors and helped develop inflammasome research.

Scientists in this field concentrated on how individual inflammasome sensors identify invading pathogens or other threats. Inflammasomes were historically considered to respond by stimulating a single inflammatory cell death pathway.

The Kanneganti lab has a lasting interest in understanding the regulation of inflammasomes and has pinpointed redundancies between cell death pathways. In 2016, scientists declared for the first time that influenza infections activated molecules in all three cell death pathways.

The researchers named the process PANoptosis. Researchers also identified that a single innate immune sensor named ZBP1 regulated PANoptosis in flu-infected cells. This research formed the basis for the advancement of the PANoptosis research field.

PANoptosomes today

At present, Kanneganti’s team has found that AIM2 is the master regulator of a new PANoptosome. The first author of the study SangJoon Lee, Ph.D., a postdoctoral fellow in the Kanneganti lab, employed immunoprecipitation, microscopy, and other methods to reveal that AIM2, other inflammasome sensors ZBP1 and Pyrin, and cell death molecules were part of this AIM2-PANoptosome. The PANoptosome induced inflammatory cell death.

This was critical evidence that the inflammasome sensors and molecules from multiple cell death pathways are in the same complex and highlighted the PANoptosome’s role in protecting the host during live pathogenic infections.”

SangJoon Lee, Study First Author and Postdoctoral Fellow, St. Jude Children’s Research Hospital

Living pathogens reveal their presence more broadly to the immune system, which helps to justify why the infections elicit PANoptosome assembly and a more vigorous immune response. Pathogens can also transport proteins that hinder the activation of specific cell death pathways. PANoptosis offers an immune system makeshift to safeguard the host.

“Our working hypothesis is that while the sensors involved may vary, most infections will induce the formation of these unique innate immune complexes called PANoptosomes to unleash inflammatory cell death, PANoptosis,” concludes Kanneganti.