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Published Online January 8, 2009
Science DOI: 10.1126/science.1169841

Reports

Submitted on December 16, 2008
Accepted on December 23, 2008

HIN-200 Proteins Regulate Caspase Activation in Response to Foreign Cytoplasmic DNA

Tara L. Roberts 1{dagger}, Adi Idris 2{dagger}, Jasmyn A. Dunn 2, Greg M. Kelly 2, Carol M. Burnton 2, Samantha Hodgson 2, Lani L. Hardy 2, Valerie Garceau 3, Matthew J. Sweet 4, Ian L. Ross 2, David A. Hume 3, Katryn J. Stacey 4*

1 The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia.; Present address: Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia.
2 The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia.
3 The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia.; Present Address: The Roslin Institute, University of Edinburgh, Roslin EH259PS, Scotland, UK.
4 The University of Queensland, School of Chemistry and Biomolecular Science, Qld 4072, Australia.

* To whom correspondence should be addressed.
Katryn J. Stacey , E-mail: k.stacey{at}imb.uq.edu.au

{dagger}These authors contributed equally to this work.

The mammalian innate immune system is activated by foreign nucleic acids. Detection of double-stranded DNA (dsDNA) in the cytoplasm triggers characteristic antiviral responses and macrophage cell death. Cytoplasmic dsDNA rapidly activated caspase 3 and caspase 1 in bone marrow-derived macrophages. We identified the HIN-200 family member and lupus susceptibility factor, p202, as a dsDNA binding protein that bound stably and rapidly to transfected DNA. Knockdown studies identified p202 as an inhibitor of DNA-induced caspase activation. Conversely, the related pyrin domain-containing HIN-200 factor, AIM2 (p210), was required for caspase activation by cytoplasmic dsDNA. This work indicates that HIN-200 proteins can act as pattern recognition receptors mediating responses to cytoplasmic dsDNA.


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