Small molecule inhibitor binds to NOD-like receptor family pyrin domain containing 3 and prevents inflammasome activation
Angela Lackner,
Julia Elise Cabral,
Yanfei Qiu,
Haitian Zhou,
Lemuel Leonidas,
Minh Anh Pham,
Alijah Macapagal,
Sophia Lin,
Emy Armanus,
Reginald McNulty
Affiliations
Angela Lackner
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Julia Elise Cabral
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Yanfei Qiu
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Haitian Zhou
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Lemuel Leonidas
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Minh Anh Pham
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Alijah Macapagal
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Sophia Lin
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Emy Armanus
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA
Reginald McNulty
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA; Corresponding author
Summary: Despite recent advances in the mechanism of oxidized DNA activating NLRP3, the molecular mechanism and consequence of oxidized DNA associating with NLRP3 remains unknown. Cytosolic NLRP3 binds oxidized DNA which has been released from the mitochondria, which subsequently triggers inflammasome activation. Human glycosylase (hOGG1) repairs oxidized DNA damage which inhibits inflammasome activation. The fold of NLRP3 pyrin domain contains amino acids and a protein fold similar to hOGG1. Amino acids that enable hOGG1 to bind and cleave oxidized DNA are conserved in NLRP3. We found NLRP3 could bind and cleave oxidized guanine within mitochondrial DNA. The binding of oxidized DNA to NLRP3 was prevented by small molecule drugs which also inhibit hOGG1. These same drugs also inhibited inflammasome activation. Elucidating this mechanism will enable the design of drug memetics that treat inflammasome pathologies, illustrated herein by NLRP3 pyrin domain inhibitors which suppressed interleukin-1β (IL-1β) production in macrophages.
