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

62 Citations (Scopus)

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)
JournalNature Immunology
DOIs
StateAccepted/In press - Jun 6 2016

Fingerprint

Protein Prenylation
Inflammasomes
Mevalonic Acid
Phosphatidylinositol 3-Kinases
Innate Immunity
Toll-Like Receptors
Mevalonate Kinase Deficiency
Inflammation
Bacterial Toxins
Familial Mediterranean Fever
Monomeric GTP-Binding Proteins
Post Translational Protein Processing
Transferases
Interleukin-1
Catalytic Domain
Macrophages
Mutation
Proteins
geranylgeranyltransferase type-I
Pyrin

ASJC Scopus subject areas

  • Immunology

Cite this

Akula, M. K., Shi, M., Jiang, Z., Foster, C. E., Miao, D., Li, A. S., ... Wang, D. (Accepted/In press). Control of the innate immune response by the mevalonate pathway. Nature Immunology. https://doi.org/10.1038/ni.3487

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 journalArticle

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 2016, 'Control of the innate immune response by the mevalonate pathway', Nature Immunology. https://doi.org/10.1038/ni.3487
Akula MK, Shi M, Jiang Z, Foster CE, Miao D, Li AS et al. Control of the innate immune response by the mevalonate pathway. Nature Immunology. 2016 Jun 6. https://doi.org/10.1038/ni.3487
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. / Control of the innate immune response by the mevalonate pathway. In: Nature Immunology. 2016.
@article{6a5e5644a04b4aa58840d6e24d1d9637,
title = "Control of the innate immune response by the mevalonate pathway",
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.",
author = "Akula, {Murali K.} and Man Shi and Zhaozhao Jiang and Foster, {Celia E.} and David Miao and Li, {Annie S.} and Xiaoman Zhang and Gavin, {Ruth M.} and Forde, {Sorcha D.} and Gail Germain and Susan Carpenter and Rosadini, {Charles V.} and Kira Gritsman and Chae, {Jae Jin} and Randolph Hampton and Neal Silverman and Gravallese, {Ellen M.} and Kagan, {Jonathan C.} and Fitzgerald, {Katherine A.} and Kastner, {Daniel L.} and Golenbock, {Douglas T.} and Bergo, {Martin O.} and Donghai Wang",
year = "2016",
month = "6",
day = "6",
doi = "10.1038/ni.3487",
language = "English (US)",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",

}

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 -