Control of the innate immune response by the mevalonate pathway.

Akula, Murali K

Shi, Man

Jiang, Zhaozhao

Foster, Celia E

Miao, David

Li, Annie S

Zhang, Xiaoman

Gavin, Ruth M

Forde, Sorcha D

Germain, Gail

Carpenter, Susan

Rosadini, Charles V

Gritsman, Kira

Chae, Jae Jin

Hampton, Randolph

Silverman, Neal

Gravallese, Ellen M

Kagan, Jonathan C

Fitzgerald, Katherine A

Kastner, Daniel L

Golenbock, Douglas T

Bergo, Martin O

Wang, Donghai

United States

2016-06-23T21:02:07Z

2016-08

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.

http://www.ncbi.nlm.nih.gov/pubmed/27270400

ni.3487

1529-2916

https://hdl.handle.net/10161/12409

eng

Springer Science and Business Media LLC

Nat Immunol

10.1038/ni.3487

Control of the innate immune response by the mevalonate pathway.

Journal article

http://www.ncbi.nlm.nih.gov/pubmed/27270400

922

929

8

Basic Science Departments

Clinical Science Departments

Duke

Immunology

Medicine

Medicine, Rheumatology and Immunology

School of Medicine

Published

17