The Inflammasome Adaptor ASC Induces Procaspase-8 Death Effector Domain Filaments

Inflammasomes mediate inflammatory and cell death responses to pathogens and cellular stress signals via activation of procaspases-1 and -8. During inflammasome assembly, activated receptors of the NLR or PYHIN family recruit the adaptor protein ASC and initiate polymerization of its pyrin domain (PYD) into filaments. We show that ASC filaments in turn nucleate procaspase-8 death effector domain (DED) filaments in vitro and in vivo. Interaction between ASC PYD and procaspase-8 tandem DEDs optimally required both DEDs and represents an unusual heterotypic interaction between domains of the death fold superfamily. Analysis of ASC PYD mutants showed that interaction surfaces that mediate procaspase-8 interaction overlap with those required for ASC self-association and interaction with the PYDs of inflammasome initiators. Our data indicate that multiple types of death fold domain filaments form at inflammasomes and that PYD/DED and homotypic PYD interaction modes are similar. Interestingly, we observed condensation of procaspase-8 filaments containing the catalytic domain, suggesting that procaspase-8 interactions within and/or between filaments may be involved in caspase-8 activation. Procaspase-8 filaments may also be relevant to apoptosis induced by death receptors. Background: ASC mediates inflammasome assembly, recruiting procaspase-1 and procaspase-8 to initiate inflammation and cell death. Results: ASC pyrin domain (PYD) surfaces that mediate filament assembly bind procaspase-8 death effector domains (DEDs) and induce filaments. Conclusion: Procaspase-8 DED filaments are initiated from ASC PYD filaments. Significance: The data give insights into cross-talk between apoptotic and inflammatory pathways and procapase-8 activation.