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Caspase-8, a key member of the caspase family, is implicated in nonlytic apoptosis, as well as lytic forms of cell death. Recently, caspase-8 has been identified as an integral component of PANoptosomes, multiprotein complexes formed in response to innate immune sensor activation. Several innate immune sensors can nucleate caspase-8\u2013containing PANoptosome complexes to drive inflammatory lytic cell death, PANoptosis. However, how the evolutionarily conserved and diverse functions of caspase-8 drive PANoptosis remains unclear. To address this, we performed evolutionary, sequence, structural, and functional analyses to decode caspase-8's complex-forming abilities and its interaction with the PANoptosome adaptor ASC. Our study distinguished distinct subgroups within the death domain superfamily based on their evolutionary and functional relationships, identified homotypic traits among subfamily members, and captured key events in caspase evolution. We also identified critical residues defining the heterotypic interaction between caspase-8's death effector domain and ASC's pyrin domain, validated through cross-species analyses, dynamic simulations, and in vitro experiments. Overall, our study elucidated recent evolutionary adaptations of caspase-8 that allowed it to interact with ASC, improving our understanding of critical molecular associations in PANoptosome complex formation and the underlying PANoptotic responses in host defense and inflammation. These findings have implications for understanding mammalian immune responses and developing new therapeutic strategies for inflammatory diseases.<\/jats:p>","DOI":"10.1093\/molbev\/msaf096","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T12:14:46Z","timestamp":1745583286000},"source":"Crossref","is-referenced-by-count":10,"title":["Evolutionary and Functional Analysis of Caspase-8 and ASC Interactions to Drive Lytic Cell Death, PANoptosis"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3461-2489","authenticated-orcid":false,"given":"Sivakumar Prasanth","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Immunology, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, TN 38105 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7938-8033","authenticated-orcid":false,"given":"Eswar Kumar","family":"Nadendla","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, TN 38105 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8855-9447","authenticated-orcid":false,"given":"R K Subbarao","family":"Malireddi","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, TN 38105 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0105-9729","authenticated-orcid":false,"given":"Syed Asfarul","family":"Haque","sequence":"additional","affiliation":[{"name":"Cryo-Electron Microscopy Center, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, TN 38105 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-3150","authenticated-orcid":false,"given":"Raghvendra","family":"Mall","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, TN 38105 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0086-5755","authenticated-orcid":false,"given":"Andrew F","family":"Neuwald","sequence":"additional","affiliation":[{"name":"Institute for Genome Sciences and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine , 670 W. 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