Molecular Mechanism for p202-Mediated Specific Inhibition of AIM2 Inflammasome Activation
Qian Yin,
David P. Sester,
Yuan Tian,
Yu-Shan Hsiao,
Alvin Lu,
Jasmyn A. Cridland,
Vitaliya Sagulenko,
Sara J. Thygesen,
Divaker Choubey,
Veit Hornung,
Thomas Walz,
Katryn J. Stacey,
Hao Wu
Affiliations
Qian Yin
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
David P. Sester
The University of Queensland, School of Chemistry and Molecular Bioscience, Brisbane QLD 4072, Australia
Yuan Tian
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA
Yu-Shan Hsiao
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Alvin Lu
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Jasmyn A. Cridland
The University of Queensland, School of Chemistry and Molecular Bioscience, Brisbane QLD 4072, Australia
Vitaliya Sagulenko
The University of Queensland, School of Chemistry and Molecular Bioscience, Brisbane QLD 4072, Australia
Sara J. Thygesen
The University of Queensland, School of Chemistry and Molecular Bioscience, Brisbane QLD 4072, Australia
Divaker Choubey
Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA
Veit Hornung
Institute for Clinical Chemistry and Clinical Pharmacology, Unit for Clinical Biochemistry, University Hospital, University of Bonn, 53127 Bonn, Germany
Thomas Walz
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Katryn J. Stacey
The University of Queensland, School of Chemistry and Molecular Bioscience, Brisbane QLD 4072, Australia
Hao Wu
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Mouse p202 containing two hemopoietic expression, interferon inducibility, nuclear localization (HIN) domains antagonizes AIM2 inflammasome signaling and potentially modifies lupus susceptibility. We found that only HIN1 of p202 binds double-stranded DNA (dsDNA), while HIN2 forms a homotetramer. Crystal structures of HIN1 revealed that dsDNA is bound on face opposite the site used in AIM2 and IFI16. The structure of HIN2 revealed a dimer of dimers, the face analogous to the HIN1 dsDNA binding site being a dimerization interface. Electron microscopy imaging showed that HIN1 is flexibly linked to HIN2 in p202, and tetramerization provided enhanced avidity for dsDNA. Surprisingly, HIN2 of p202 interacts with the AIM HIN domain. We propose that this results in a spatial separation of the AIM2 pyrin domains, and indeed p202 prevented the dsDNA-dependent clustering of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) and AIM2 inflammasome activation. We hypothesize that while p202 was evolutionarily selected to limit AIM2-mediated inflammation in some mouse strains, the same mechanism contributes to increased interferon production and lupus susceptibility.
