Control of the innate immune response by the mevalonate pathway.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Akula, MK; Shi, M; Jiang, Z; Foster, CE; Miao, D; Li, AS; Zhang, X; Gavin, RM; Forde, SD; Germain, G; Carpenter, S; Rosadini, CV; Gritsman, K; Chae, JJ; Hampton, R; Silverman, N; Gravallese, EM; Kagan, JC; Fitzgerald, KA; Kastner, DL; Golenbock, DT; Bergo, MO; Wang, D

Published Date

  • August 2016

Published In

Volume / Issue

  • 17 / 8

Start / End Page

  • 922 - 929

PubMed ID

  • 27270400

Pubmed Central ID

  • PMC4955724

Electronic International Standard Serial Number (EISSN)

  • 1529-2916

Digital Object Identifier (DOI)

  • 10.1038/ni.3487


  • eng

Conference Location

  • United States