Gasdermins are ancient immune proteins

Gasdermins have crucial roles in inflammasome-mediated immune responses in human. Gasdermin is normally inactive in the cell owing to an inhibitory C-terminal domain that physically sequesters its N-terminal domain. Upon sensing of a pathogen infection, inflammasome-activated caspases cleave off the C-terminal domain of gasdermin, which releases the active N-terminal domain to oligomerize and form large pores in the membrane. Gasdermin-mediated pore formation promotes cell death, during which active IL-1β and IL-18 are released from the cell through the gasdermin pores. 

Our recent study identified gasdermins in bacteria and archaea and showed that these have high levels of structural homology to the mammalian proteins (Johnson & Wein et al., Science 2022). Similarly to eukaryotic gasdermins, prokaryotic gasdermins are processed by proteases that remove a C-terminal inhibitory peptide from gasdermin and activate it to oligomerize and form large membrane pores. Gasdermin-mediated anti-phage defense depends on an intact gasdermin protein as well as on the protease, and involved premature cell death of the infected bacterium. Therefore, bacterial gasdermins are not only structurally similar to mammalian gasdermins but are also similarly activated by dedicated proteases and defend against pathogen propagation by inducing pore-mediated premature cell death.

We recently found that the gasdermin operon originating from the bacterium Lysobacter enzymogenes comprises, in addition to the gasdermin gene, two consecutive genes encoding proteins with trypsin-like protease domains, and a gene encoding a protein annotated as an ATPase that are essential for anti-phage defense (Wein & Johnson et al., bioRxiv, 2023). A closer examination of the domain architecture of the ATPase showed that it belongs to the STAND ATPase protein family, which are bacterial proteins that are considered the evolutionary ancestors of eukaryotic NLR immune receptors. While analyzing the domain architectures of the system we further found that both the protease and the NLR-like gene contain a domain that is highly similar to the human caspase recruitment domain (CARD). CARD domains belong to the super family of death domains and are essential adaptor domains that facilitate protein-protein interactions in the human immune system. The Lysobacter gasdermin operon architecture therefore implies that in bacteria pyroptosis may be initiated by a pattern recognition NLR-like protein and that the signal of infection may be transferred via CARD-like domains activating the protease which cleaves gasdermin akin to pyroptosis regulation in human cells. This discovery is the first to report the potential conservation of a full immune pathway present as an operon in bacteria remaining active in the mammalian immune system.