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Nat Immunol. 2016 Aug;17(8):922-9. doi: 10.1038/ni.3487. Epub 2016 Jun 6.

Control of the innate immune response by the mevalonate pathway.

Author information

1
Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
2
Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
3
Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
4
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
5
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Medicine, Albert Einstein College of Medicine, New York City, New York, USA.
7
Department of Cell Biology, Albert Einstein College of Medicine, New York City, New York, USA.
8
Inflammatory Disease Section, Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
9
Division of Biology, University of California San Diego, La Jolla, California, USA.
10
Division of Rheumatology, Department of Medicine, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Abstract

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

PMID:
27270400
PMCID:
PMC4955724
DOI:
10.1038/ni.3487
[Indexed for MEDLINE]
Free PMC Article

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