Control of the innate immune response by the mevalonate pathway.
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.
Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.|Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Murali K
MK
Akula
Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Man
M
Shi
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Zhaozhao
Z
Jiang
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Celia E
CE
Foster
Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
David
D
Miao
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Annie S
AS
Li
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Xiaoman
X
Zhang
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Ruth M
RM
Gavin
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Sorcha D
SD
Forde
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Gail
G
Germain
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Susan
S
Carpenter
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Charles V
CV
Rosadini
Department of Medicine, Albert Einstein College of Medicine, New York City, New York, USA.|Department of Cell Biology, Albert Einstein College of Medicine, New York City, New York, USA.
Kira
K
Gritsman
Inflammatory Disease Section, Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Jae Jin
JJ
Chae
Division of Biology, University of California San Diego, La Jolla, California, USA.
Randolph
R
Hampton
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Neal
0000-0002-4259-456X
N
Silverman
Division of Rheumatology, Department of Medicine, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Ellen M
EM
Gravallese
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Jonathan C
JC
Kagan
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Katherine A
KA
Fitzgerald
Inflammatory Disease Section, Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Daniel L
DL
Kastner
Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Douglas T
DT
Golenbock
Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Martin O
MO
Bergo
Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.|Division of Infectious Diseases and Immunology, the University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Donghai
D
Wang
D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D010505:Familial Mediterranean Fever / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D000071198:Pyrin / Q000235:genetics*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
D058847:Inflammasomes; D053583:Interleukin-1beta; D011106:Polyisoprenyl Phosphates; D000071198:Pyrin; D051193:Toll-Like Receptors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; C002963:geranylgeranyl pyrophosphate