Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency

Politiek, Frouwkje A.; Waterham, Hans R.

doi:10.3389/fimmu.2021.724991

Cited by 31 publications

(42 citation statements)

References 129 publications

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“…Consistently, in vitro studies of cells from patients with HIDS demonstrate a reduced ability to clear antioxidant stress, as well as mitochondrial dysfunction and deficiency in autophagy, all of which are implicated in inflammasome activation 35 . More recent evidence in human and murine models suggests that the post-translational modification and subsequent attachment of isoprenoids to GTPases, including the Rho, Rac and Rap families of GTPases, are significantly affected by reduced mevalonate kinase activity 76 , ultimately leading to increased IL-1β secretion from monocytes, likely in a pyrin inflammasome-dependent fashion 36 , 77 . The successful use of IL-1-targeted therapy in HIDS is evidence that supports these pathogenic mechanisms 71 .…”

Section: Aetiology Of Autoinflammatory Diseasesmentioning

confidence: 99%

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

Broderick

Hoffman

2022

Nat Rev Rheumatol

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Over 20 years ago, it was first proposed that autoinflammation underpins a handful of rare monogenic disorders characterized by recurrent fever and systemic inflammation. The subsequent identification of novel, causative genes directly led to a better understanding of how the innate immune system is regulated under normal conditions, as well as its dysregulation associated with pathogenic mutations. Early on, IL-1 emerged as a central mediator for these diseases, based on data derived from patient cells, mutant mouse models and definitive clinical responses to IL-1 targeted therapy. Since that time, our understanding of the mechanisms of autoinflammation has expanded beyond IL-1 to additional innate immune processes. However, the number and complexity of IL-1-mediated autoinflammatory diseases has also multiplied to include additional monogenic syndromes with expanded genotypes and phenotypes, as well as more common polygenic disorders seen frequently by the practising clinician. In order to increase physician awareness and update rheumatologists who are likely to encounter these patients, this review discusses the general pathophysiological concepts of IL-1-mediated autoinflammation, the epidemiological and clinical features of specific diseases, diagnostic challenges and approaches, and current and future perspectives for therapy.

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Section: Aetiology Of Autoinflammatory Diseasesmentioning

confidence: 99%

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

Broderick

Hoffman

2022

Nat Rev Rheumatol

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“…Increased flux through the mevalonate pathway enhances posttranslational modification of Rac1, promoting macrophage/fibroblast signaling ( Larson-Casey et al, 2014 , 2016 ; Politiek and Waterham, 2021 ). Further elucidation of this mechanism was conducted by probing the downstream signaling pathway ( Figure 6A ) by assessing farnesyl diphosphate synthase (FDPS).…”

Section: Resultsmentioning

confidence: 99%

Zoledronic Acid Targeting of the Mevalonate Pathway Causes Reduced Cell Recruitment and Attenuates Pulmonary Fibrosis

et al. 2022

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Background and aim: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreparable scarring of lung tissue, with most patients succumbing rapidly after diagnosis. The mevalonate pathway, which is involved in the regulation of cell proliferation, survival, and motility, is targeted by the bisphosphonate zoledronic acid (ZA). The aim of this study was to assess the antifibrotic effects of ZA and to elucidate the mechanisms by which potential IPF treatment occurs.Methods: A series of in vitro and in vivo models were employed to identify the therapeutic potential of ZA in treating IPF. In vitro transwell assays were used to assess the ability of ZA to reduce fibrotic-related immune cell recruitment. Farnesyl diphosphate synthase (FDPS) was screened as a potential antifibrotic target using a bleomycin mouse model. FDPS-targeting siRNA and ZA were administered to mice following the onset of experimentally-induced lung fibrosis. Downstream analyses were conducted on murine lung tissues and lung fluids including 23-plex cytokine array, flow cytometry, histology, Western blotting, immunofluorescent staining, and PCR analysis.Results:In vitro administration of ZA reduced myofibroblast transition and blocked NF-κB signaling in macrophages leading to impaired immune cell recruitment in a transwell assay. FDPS-targeting siRNA administration significantly attenuated profibrotic cytokine production and lung damage in a murine lung fibrosis model. Furthermore, ZA treatment of mice with bleomycin-induced lung damage displayed decreased cytokine levels in the BALF, plasma, and lung tissue, resulting in less histologically visible fibrotic scarring. Bleomycin-induced upregulation of the ZA target, FDPS, was reduced in lung tissue and fibroblasts upon ZA treatment. Confirmatory increases in FDPS immunoreactivity was seen in human IPF resected lung samples compared to control tissue indicating potential translational value of the approach. Additionally, ZA polarized macrophages towards a less profibrotic phenotype contributing to decreased IPF pathogenesis.Conclusion: This study highlights ZA as an expedient and efficacious treatment option against IPF in a clinical setting.

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“…The aetiopathogenesis of autoinflammation in MKD has not been fully elucidated yet, although recent studies emphasise the role of defective prenylation in RhoA inactivation ( 27 ). Mevalonate kinase (MVK) is a central enzyme catalysing the isoprenoid biosynthesis pathway, generating sterol and non-sterol isoprenoids utilised in essential cellular functions ( 55 ). Autoinflammation and pyrin inflammasome activation in MKD has indicated the role of isoprenoids in the regulatory innate immune mechanisms ( 55 ).…”

Section: Mevalonate Kinase Deficiency or Hyperimmunoglobulin D With P...mentioning

confidence: 99%

“…Mevalonate kinase (MVK) is a central enzyme catalysing the isoprenoid biosynthesis pathway, generating sterol and non-sterol isoprenoids utilised in essential cellular functions ( 55 ). Autoinflammation and pyrin inflammasome activation in MKD has indicated the role of isoprenoids in the regulatory innate immune mechanisms ( 55 ). Downstream molecules in cholesterol biosynthesis such as geranylgeranyl pyrophosphate (GGPP) were shown to be used in protein prenylation by post-translational attachment of these molecules to the target proteins for optimum membrane localisation ( 55 , 56 ).…”

Section: Mevalonate Kinase Deficiency or Hyperimmunoglobulin D With P...mentioning

confidence: 99%

“…Autoinflammation and pyrin inflammasome activation in MKD has indicated the role of isoprenoids in the regulatory innate immune mechanisms ( 55 ). Downstream molecules in cholesterol biosynthesis such as geranylgeranyl pyrophosphate (GGPP) were shown to be used in protein prenylation by post-translational attachment of these molecules to the target proteins for optimum membrane localisation ( 55 , 56 ). As an explanatory mechanism, Park et al ( 27 ) demonstrated that membrane targetting of RhoA was also dependent on geranylgeranylation, which was compromised in the absence of GGPP resulting in RhoA inactivation and consequent pyrin inflammasome activation.…”

Section: Mevalonate Kinase Deficiency or Hyperimmunoglobulin D With P...mentioning

confidence: 99%

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Hereditary Systemic Autoinflammatory Diseases: Therapeutic Stratification

et al. 2022

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Hereditary systemic autoinflammatory diseases (SAIDs) are rare, often severe conditions characterised by mutations in the key regulators of innate immune responses. Dramatic advances in the molecular genetics and next-generation sequencing in the past decade enabled identification of novel mutations that play a pivotal role in the mechanistic pathways of inflammation. Although genetic testing may not always provide straightforward guidance in diagnosis and clinical decision making, through translational research, it sheds light into molecular immunopathogenesis, particularly in IL-1 inflammasome and cytokine signalling pathways. These remarkable insights provided a better understanding of autoinflammatory conditions and their association with the innate and adaptive immune systems, as well as leading to development of cytokine-targetted biologic treatments. Use of targetted therapeutics not only helps control disease flares, reduce acute-phase responses and prevent devastating complications such as amyloidosis, but also improves health-related quality of lives and support patients to pursue almost a normal life. Herein, we discuss the commonest monogenic SAIDs, describe their immunopathology, and summarise the approaches in the management and targetted treatment of these conditions, including presentation of novel data based on a cohort of children with these rare diseases from a single quaternary referral centre in London.

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Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency

Cited by 31 publications

References 129 publications

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

Zoledronic Acid Targeting of the Mevalonate Pathway Causes Reduced Cell Recruitment and Attenuates Pulmonary Fibrosis

Hereditary Systemic Autoinflammatory Diseases: Therapeutic Stratification

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