Cell death executioners driving PANoptosis 2259603

Abstract Introduction Cell death is a key effector mechanism to maintain homeostasis and drive immune activation and host defense. However, excess cell death is linked to inflammation, pathology, and disease. Therefore, balancing the execution of cell death is critical. To control this process, executioner proteins form membrane pores that drive cell lysis and the release of damage-associated molecular patterns (DAMPs) and cytokines. Different executioners have been implicated across cell death pathways. In certain pathways, such as pyroptosis or necroptosis, a single executioner is critical (gasdermin D (GSDMD) and MLKL, respectively). However, in PANoptosis, an innate immune, inflammatory cell death pathway driven by caspases and RIPKs, multiple executioners are activated. Given the increasing recognition of PANoptosis as a key driver of inflammation and pathology in infections and inflammatory conditions, understanding the specific roles of these executioners is critical for identifying therapeutic targets. However, this understanding is currently lacking. Methods We have performed a comprehensive genetic analysis to define the roles of GSDMD, GSDME, and MLKL, the primary pore-forming molecules known to be activated in PANoptosis, in driving cell death in response to a diverse array of pathogen and sterile triggers that are known to induce PANoptosis by activating different innate immune sensors. By utilizing a large number of genetic models, including single, double, and triple knockout systems, to assess the individual and redundant functions of each executioner. Results Our study provides a holistic view of how executioners contribute to PANoptosis in response to diverse stimuli. The executioners can act in a redundant manner to execute PANoptosis. Conclusion These findings demonstrate the potential therapeutic value of targeting executioner molecules for the treatment of diverse infections and inflammatory diseases. Funding Source This research was supported by NIH grants AI101935, AI124346, AI160179, AR056296, and CA253095 and the American Lebanese Syrian Associated Charities to Dr. Kanneganti. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)