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J Biol Chem. 2015 Dec 4;290(49):29217-30. doi: 10.1074/jbc.M115.687731. Epub 2015 Oct 14.

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

Author information

1
From the School of Chemistry and Molecular Biosciences and.
2
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.
3
the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
4
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.
5
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.

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.

KEYWORDS:

apoptosis; caspase; cell death; death domain; death domain filaments; inflammasome; pattern recognition receptor (PRR)

PMID:
26468282
PMCID:
PMC4705927
DOI:
10.1074/jbc.M115.687731
[Indexed for MEDLINE]
Free PMC Article

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