Small molecule inhibitor binds to NOD-like receptor family pyrin domain containing 3 and prevents inflammasome activation
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Abstract
Abstract 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 design of drug memetics that treat inflammasome pathologies, illustrated herein by NLRP3 pyrin domain inhibitors which suppressed interleukin-1β (IL-1β) production in macrophages. One-Sentence Summary NLRP3 cleaves oxidized DNA and small molecule drug binding inhibits inflammasome activation.
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Cites
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- Authors
- Lackner, A., Cabral, J. E., Qiu, Y., Zhou, H., Leonidas, L., Pham, M. A., Macapagal, A., Lin, S., Armanus, E., & McNulty, R.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- McNulty, Reginald
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2024-08
- Volume
- 27
- Issue
- 8
- Pages
- 110459
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC11298654
- OpenAlex
- W4400338972
- Cited by
- 16
- References
- 4
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 2
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- PubMed Central (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- NIAID (K22AI139444)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- NLRP3 inflammasome, pyrin domain, oxidized DNA, OGG1, small molecule inhibitors, mitochondrial DNA, oxidized guanine, DNA repair, IL-1β, macrophages, inflammasome activation, drug design
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