Related Experiment Video
Updated: Jul 19, 2026
09:04
Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
A role for geranylgeranylation in interleukin-1beta secretion.
Saskia H L Mandey1, Loes M Kuijk, Joost Frenkel
1Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Arthritis and Rheumatism
|November 1, 2006
Summary
Mevalonate kinase deficiency (MKD) causes inflammation due to a shortage of geranylgeranylated proteins, not excess mevalonic acid. Supplementing with geranylgeranyl pyrophosphate (GGPP) reversed this interleukin-1beta (IL-1beta) secretion in patients.
Area of Science:
- Biochemistry
- Immunology
- Genetics
Background:
- Mevalonate kinase deficiency (MKD) is an autosomal-recessive disorder causing recurrent inflammatory episodes.
- Mevalonate kinase (MK) is crucial for isoprenoid biosynthesis, impacting cellular functions.
Purpose of the Study:
- To investigate if isoprenoid end-product deficiency or mevalonic acid accumulation causes interleukin-1beta (IL-1beta) secretion in MKD.
- To elucidate the underlying mechanisms of inflammation in MKD.
Main Methods:
- Studied the impact of isoprenoid pathway metabolites and inhibitors on IL-1beta secretion in patient and control peripheral blood mononuclear cells (PBMCs).
- Utilized supplementation with geranylgeranyl pyrophosphate (GGPP) and mevalonic acid to assess effects on IL-1beta secretion.
Main Results:
- Inhibition of GGPP synthesis or geranylgeranylation increased IL-1beta secretion in control PBMCs.
- GGPP and mevalonic acid supplementation reversed elevated IL-1beta secretion in MKD PBMCs.
- Excess mevalonic acid alone increased IL-1beta secretion in controls, while inhibiting sterol synthesis favored nonsterol isoprenoid production.
Conclusions:
- A shortage of geranylgeranylated proteins, not excess mevalonate, is the likely cause of increased IL-1beta secretion in MKD.
- Targeting isoprenoid biosynthesis may offer therapeutic strategies for managing inflammation in MKD.
Related Concept Videos
01:11IP3/DAG Signaling Pathway
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
02:26NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...