title: The Inflammasome Adaptor ASC Induces Procaspase-8 Death Effector Domain Filaments.
abstract: 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.
authors.affiliation: From the School of Chemistry and Molecular Biosciences and.
authors.forename: Parimala R
authors.initials: PR
authors.lastname: Vajjhala
authors.affiliation: the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, and the Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115.
authors.forename: Alvin
authors.initials: A
authors.lastname: Lu
authors.affiliation: the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Darren L
authors.initials: DL
authors.lastname: Brown
authors.affiliation: From the School of Chemistry and Molecular Biosciences and.
authors.forename: Siew Wai
authors.initials: SW
authors.lastname: Pang
authors.affiliation: From the School of Chemistry and Molecular Biosciences and.
authors.forename: Vitaliya
authors.initials: V
authors.lastname: Sagulenko
authors.affiliation: From the School of Chemistry and Molecular Biosciences and.
authors.forename: David P
authors.initials: DP
authors.lastname: Sester
authors.affiliation: From the School of Chemistry and Molecular Biosciences and.
authors.forename: Simon O
authors.initials: SO
authors.lastname: Cridland
authors.affiliation: From the School of Chemistry and Molecular Biosciences and.
authors.forename: Justine M
authors.initials: JM
authors.lastname: Hill
authors.affiliation: the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.affiliation: the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
authors.affiliation: the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, and the Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115 hao.wu@childrens.harvard.edu.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: From the School of Chemistry and Molecular Biosciences and the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia, katryn.stacey@uq.edu.au.
authors.forename: Katryn J
authors.initials: KJ
authors.lastname: Stacey
mesh_terms: D017209:Apoptosis; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D020134:Catalytic Domain; D016923:Cell Death; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation; D008856:Microscopy, Fluorescence; D009154:Mutation; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C402202:PYCARD protein, human; C505530:CASP8 protein, human; D053181:Caspase 8; D020170:Caspase 1
keywords: apoptosis; caspase; cell death; death domain; death domain filaments; inflammasome; pattern recognition receptor (PRR)