Control of the innate immune response by the mevalonate pathway

Murali K. Akula, Man Shi, Zhaozhao Jiang, Celia E. Foster, David Miao, Annie S. Li, Xiaoman Zhang, Ruth M. Gavin, Sorcha D. Forde, Gail Germain, Susan Carpenter, Charles V. Rosadini, Kira Gritsman, Jae Jin Chae, Randolph Hampton, Neal Silverman, Ellen M. Gravallese, Jonathan C. Kagan, Katherine A. Fitzgerald, Daniel L. KastnerDouglas T. Golenbock, Martin O. Bergo, Donghai Wang

Research output: Contribution to journalArticle

68 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)922-929
Number of pages8
JournalNature Immunology
Volume17
Issue number8
DOIs
StatePublished - Jul 19 2016

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Akula, M. K., Shi, M., Jiang, Z., Foster, C. E., Miao, D., Li, A. S., Zhang, X., Gavin, R. M., Forde, S. D., Germain, G., Carpenter, S., Rosadini, C. V., Gritsman, K., Chae, J. J., Hampton, R., Silverman, N., Gravallese, E. M., Kagan, J. C., Fitzgerald, K. A., ... Wang, D. (2016). Control of the innate immune response by the mevalonate pathway. Nature Immunology, 17(8), 922-929. https://doi.org/10.1038/ni.3487