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 language | English (US) |
|---|---|
| Journal | Nature Immunology |
| DOIs | |
| State | Accepted/In press - Jun 6 2016 |
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ASJC Scopus subject areas
- Immunology
Cite this
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.
In: Nature Immunology, 06.06.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Control of the innate immune response by the mevalonate pathway
AU - Akula, Murali K.
AU - Shi, Man
AU - Jiang, Zhaozhao
AU - Foster, Celia E.
AU - Miao, David
AU - Li, Annie S.
AU - Zhang, Xiaoman
AU - Gavin, Ruth M.
AU - Forde, Sorcha D.
AU - Germain, Gail
AU - Carpenter, Susan
AU - Rosadini, Charles V.
AU - Gritsman, Kira
AU - Chae, Jae Jin
AU - Hampton, Randolph
AU - Silverman, Neal
AU - Gravallese, Ellen M.
AU - Kagan, Jonathan C.
AU - Fitzgerald, Katherine A.
AU - Kastner, Daniel L.
AU - Golenbock, Douglas T.
AU - Bergo, Martin O.
AU - Wang, Donghai
PY - 2016/6/6
Y1 - 2016/6/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84976313489&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84976313489&partnerID=8YFLogxK
U2 - 10.1038/ni.3487
DO - 10.1038/ni.3487
M3 - Article
C2 - 27270400
AN - SCOPUS:84976313489
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
ER -