Skip to main content
Article
Control of the innate immune response by the mevalonate pathway
University of Massachusetts Medical School Faculty Publications
  • Zhaozhao Jiang, University of Massachusetts Medical School
  • Celia E. Foster, University of Massachusetts Medical School
  • Annie S. Li, University of Massachusetts Medical School
  • Xiaoman Zhang, University of Massachusetts Medical School
  • Ruth M. Gavin, University of Massachusetts Medical School
  • Sorcha D. Forde, University of Massachusetts Medical School
  • Gail Germain, University of Massachusetts Medical School
  • Susan B. Carpenter, University of Massachusetts Medical School
  • Neal S. Silverman, University of Massachusetts Medical School
  • Ellen M. Gravallese, University of Massachusetts Medical School
  • Katherine A. Fitzgerald, University of Massachusetts Medical School
  • Douglas T. Golenbock, University of Massachusetts Medical School
  • Donghai Wang, University of Massachusetts Medical School
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology; Department of Medicine, Division of Rheumatology
Date
8-1-2016
Document Type
Article
Disciplines
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 p110delta. Macrophages that were deficient in GGTase I or p110delta exhibited constitutive release of interleukin 1beta 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.
Rights and Permissions
Citation: Nat Immunol. 2016 Aug;17(8):922-9. doi: 10.1038/ni.3487. Epub 2016 Jun 6. Link to article on publisher's site
Comments

Full author list omitted for brevity. For full list see article.

Related Resources
Link to Article in PubMed
PubMed ID
27270400
Citation Information
Zhaozhao Jiang, Celia E. Foster, Annie S. Li, Xiaoman Zhang, et al.. "Control of the innate immune response by the mevalonate pathway" Vol. 17 Iss. 8 (2016) ISSN: 1529-2908 (Linking)
Available at: http://works.bepress.com/neal_silverman/71/