Receptor interacting protein kinase 2–mediated mitophagy regulates inflammasome activation during virus infection
Open accessAbstract
NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2(-/-) and Ripk2(-/-) mice are hypersusceptible to infection with influenza A virus. Ripk2(-/-) cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1(-/-) cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.
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These results suggest that mitophagy is a driver of LPS-induced mitochondrial protein degradation in DCs.
“These results suggest that mitophagy is a driver of LPS induced mitochondrial protein degradation in DCs, consistent with previous observations of mitophagy in virus- or bacteria-infected DCs (44) and might also contribute to epitope presentation, as previously proposed (45).”
From Dynamic profiling of the protein life cycle in response to pathogens (2015) · cites this paper as [44]
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- Authors
- Lupfer, C., Thomas, P. G., Anand, P. K., Vogel, P., Milasta, S., Martinez, J., Huang, G., Green, M., Kundu, M., Chi, H., Xavier, R. J., Green, D. R., Lamkanfi, M., Dinarello, C. A., Doherty, P. C., & Kanneganti, T.-D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Broad Institute (US)
- Vlaams Instituut voor Biotechnologie (BE)
- University of Colorado Denver (US)
- Corresponding author
- Kanneganti, Thirumala-Devi
- ORCID
- Venue
- Nature Immunology
- Published
- 2013-03-24
- Volume
- 14
- Issue
- 5
- Pages
- 480-488
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3631456
- OpenAlex
- W2157352436
- Cited by
- 384
- References
- 52
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 20 · 2023: 28 · 2022: 32 · 2021: 30 · 2020: 42 · 2019: 27 · 2018: 39 · 2017: 27 · 2016: 31 · 2015: 25 · 2014: 34 · 2013: 17
- FWCI
- 15.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BearWorks (Missouri State University) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL114697)
- National Cancer Institute (R01CA163507, CA163507)
- National Institute of Allergy and Infectious Diseases (R01AI044828, AI101935, R01AI101935, R01AI047891, R37AI101935)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056296, AR-056296)
- FP7 Ideas: European Research Council (281600)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- RIPK2, mitophagy, NLRP3 inflammasome, influenza A virus, viral infection, NOD2, ULK1, IL-18, superoxide, caspase-1, autophagy, inflammation
- MeSH terms
- Autophagy-Related Protein-1 Homolog, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Cells, Cultured, Immunity, Active, Mice, Inbred C57BL, Mitochondria, Orthomyxoviridae Infections, Superoxides, Signal Transduction, Protein Serine-Threonine Kinases, Mice, Knockout, Caspase 1, Interleukin-18, Alphainfluenzavirus, Virulence Factors, Mice, Nod2 Signaling Adaptor Protein, Receptor-Interacting Protein Serine-Threonine Kinase 2, Inflammasomes, Mitophagy
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