المؤلفون: Frouwkje A. Politiek, Hans R. Waterham

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: mevalonate kinase deficiency (MKD), protein prenylation, hyper IgD syndrome, mevalonic aciduria, isoprenoid biosynthesis, Immunologic diseases. Allergy, RC581-607

الوصف: Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.724991/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/31f6d2a4c60e46088d9662520a8d229cTest

المؤلفون: Gregory Swan, Jia Geng, Eunchong Park, Quanquan Ding, John Zhou, Ciana Walcott, Junyi J. Zhang, Hsin-I Huang, Gianna Elena Hammer, Donghai Wang

المصدر: Frontiers in Immunology, Vol 12 (2021)
Frontiers in Immunology

مصطلحات موضوعية: Chemokine, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, T cell, Immunology, Protein Prenylation, T cells, Biology, Mice, Chemokine receptor, Immune system, Heterotrimeric G protein, medicine, Animals, Immunology and Allergy, lymphocyte migration, Original Research, protein geranylgeranylation, autoimmunity, Correction, FOXP3, Cell Differentiation, RC581-607, Acquired immune system, adaptive immune response, Cell biology, body regions, Chemotaxis, Leukocyte, medicine.anatomical_structure, biology.protein, Th17 Cells, Receptors, Chemokine, Lipid modification, Immunologic diseases. Allergy, Signal Transduction

الوصف: Precisely controlled lymphocyte migration is critically required for immune surveillance and successful immune responses. Lymphocyte migration is strictly regulated by chemokines and chemokine receptors. Here we show that protein geranylgeranylation, a form of post-translational protein lipid modification, is required for chemokine receptor-proximal signaling. Mature thymocytes deficient for protein geranylgeranylation are impaired for thymus egress. Circulating mature T cells lacking protein geranylgeranylation fail to home to secondary lymphoid organs or to transmigrate in response to chemokines in vitro. Mechanistically, protein geranylgeranylation modifies the γ-subunits of the heterotrimeric small GTPases that are essential for chemokine receptor signaling. In addition, protein geranylgeranylation also promotes the differentiation of IL-17-producing T helper cells while inhibiting the differentiation of Foxp3+ regulatory T cells. Finally, mice with T cell lineage-specific deficiency of protein geranylgeranylation are resistant to experimental autoimmune encephalomyelitis induction. This study elucidated a critical role of protein geranylgeranylation in regulating T lymphocyte migration and function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ea78181d227cbc9959a1725f0a99d1c9Test
https://www.frontiersin.org/articles/10.3389/fimmu.2021.641188/fullTest

المؤلفون: Rob J.W. Arts, David Coman, Michael J. Rogers, Marcia A. Munoz, Julie Jurczyluk, Christina Boros, Sam Mehr, Anna Simon, Pravin Hissaria

المصدر: Frontiers in Immunology, Vol 10 (2019)
Frontiers in Immunology, 10
Frontiers in Immunology

مصطلحات موضوعية: Adult, Male, lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Genotype, Immunology, Protein Prenylation, Biology, Compound heterozygosity, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Prenylation, medicine, Humans, Immunology and Allergy, Phosphorylation, Child, Cells, Cultured, Original Research, Rap1, Mevalonate kinase deficiency, mevalonate kinase, Hereditary Autoinflammatory Diseases, rap1 GTP-Binding Proteins, Mevalonate kinase, HIDS, prenylation, autoinflammation, medicine.disease, Molecular biology, 3. Good health, Phosphotransferases (Alcohol Group Acceptor), 030104 developmental biology, Mevalonic aciduria, Mutation, Leukocytes, Mononuclear, biology.protein, Protein prenylation, Female, Rab, Mevalonate Kinase Deficiency, lcsh:RC581-607, Biomarkers, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Rab GTPase, 030215 immunology

الوصف: The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the MVK gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases. We have now analyzed PBMCs from an additional six patients with genetically-confirmed MKD (with different compound heterozygous MVK genotypes), and compared these with PBMCs from three healthy volunteers and four unaffected control individuals heterozygous for the commonest pathogenic variant, MVKV377I. We detected a clear accumulation of unprenylated Rab proteins, as well as unprenylated Rap1A by western blotting, in all six genetically-confirmed MKD patients compared to heterozygous controls and healthy volunteers. Furthermore, in the three subjects for whom measurements of residual mevalonate kinase activity was available, enzymatic activity inversely correlated with the extent of the defect in protein prenylation. Finally, a heterozygous MVKV377I patient presenting with autoinflammatory symptoms did not have defective prenylation, indicating a different cause of disease. These findings support the notion that the extent of loss of enzyme function caused by biallelic MVK variants determines the severity of defective protein prenylation, and the accumulation of unprenylated proteins in PBMCs may be a sensitive and consistent biomarker that could be used to aid, or help rule out, diagnosis of MKD.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d9bc3ceb14542a58d80ad081ac59942aTest
https://doi.org/10.3389/fimmu.2019.01900Test

المصدر: Frontiers in Immunology.

مصطلحات موضوعية: 0301 basic medicine, Cell type, biology, Chemistry, medicine.medical_treatment, Immunology, Farnesyltransferase inhibitor, Degranulation, Immunoglobulin E, Mast cell, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Cytokine, medicine.anatomical_structure, medicine, biology.protein, Immunology and Allergy, Protein prenylation, Protein kinase B, 030215 immunology

الوصف: Mast cells are major effector cells in immunoglobulin E (IgE)-mediated allergy. The high affinity IgE receptor FceRI, as well as G protein-coupled receptors (GPCRs) on the mast cell surface signal to phosphoinositide 3-kinase gamma (PI3Kgamma) to initiate degranulation, cytokine release and chemotaxis. PI3Kgamma is therefore considered as a target for treatment of allergic disorders. However, leukocyte PI3Kgamma is key to many functions in innate and adaptive immunity, and attenuation of host defense mechanisms is an expected adverse effect that complicates treatment of chronic illnesses. PI3Kgamma operates as a p110gamma/p84 or p110gamma/p101 complex, where p110gamma/p84 requires Ras activation. Here we investigated if modulation of Ras-isoprenylation could target PI3Kgamma activity to attenuate PI3Kgamma-dependent mast cell responses without impairment of macrophage functions. In murine bone marrow-derived mast cells, GPCR stimulation triggers activation of N-Ras and H-Ras isoforms, which is followed by the phosphorylation of protein kinase B (PKB/Akt) relayed through PI3Kgamma. Although K-Ras is normally not activated in Ras wild-type cells, it is able to compensate for genetically deleted N- and H-Ras isoforms. Inhibition of Ras isoprenylation with farnesyltransferase inhibitor FTI-277 leads to a significant reduction of mast cell degranulation, cytokine production and migration. Complementation experiments expressing PI3Kgamma adaptor proteins p84 or p101 demonstrated a differential sensitivity towards Ras-inhibition depending on PI3Kgamma complex composition. Mast cell responses are exclusively p84-dependent, and were effectively controlled by FTI-277. Similar results were obtained when GTP-Ras was inactivated by overexpression of the GAP-domain of Neurofibromin-1 (NF-1). Unlike mast cells, macrophages express p84 and p101, but are p101-dominated and thus remain functional under treatment with FTI-277. Our work demonstrates that p101 and p84 have distinct physiological roles and that Ras dependence of PI3Kgamma signaling differs between cell types. FTI-277 reduces GPCR-activated PI3Kgamma responses in p84-expressing but not p101-containing bone marrow derived cells. However, prenylation inhibitors have pleiotropic effects beyond Ras and non-tolerable side-effects that disfavor further clinical validation. Statins are, however, clinically well-established drugs that have previously been proposed to block mast cell degranulation by interference with protein prenylation. We show here that Simvastatin inhibits mast cell degranulation, but that this does not occur via Ras-PI3Kgamma pathway alterations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::16af6065d3ed56e9482eb636980a1aebTest