Unprenylated RhoA Contributes to IL-1β Hypersecretion in Mevalonate Kinase Deficiency Model through Stimulation of Rac1 Activity

Burgh, Robert van der; Pervolaraki, Kalliopi; Turkenburg, Marjolein; Waterham, Hans R.; Frenkel, Joost; Boes, Marianne

doi:10.1074/jbc.m114.571810

Cited by 48 publications

(39 citation statements)

References 38 publications

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“…A recent work in patients with rheumatoid arthritis demonstrated that increasing autophagic flux could be beneficial toward lowering markers of inflammation [35] and a previous study also demonstrated that everolimus (inhibitor of mTor pathway) treatment, concomitant with methotrexate, could improve symptoms of patients suffering of rheumatoid arthritis [36]. Van der Burgh and co-authors have previously shown that treatment of MKD patients’ monocyte with rampamycin, inhibitor of mTor pathway, slightly diminish IL-1β secretion after LPS challenge, although not to levels similar to the control [37]. These data showed how autophagy is a complex process and other possibly involved molecules need to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Tricarico

Romeo

Gratton

et al. 2017

Cell Physiol Biochem

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Background/Aims: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. Methods: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. Results: MVK mutants’ over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. Conclusions: We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation.

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Section: Discussionmentioning

confidence: 99%

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Tricarico

Romeo

Gratton

et al. 2017

Cell Physiol Biochem

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“…Inhibition of Rac1 in THP-1 monocyte cultures prevented IL-1β overproduction driven by impaired cholesterol biosynthesis (80). In the HIDS models, RhoA inactivity increased IL-1β gene transcription (signal 1) and thus provided a mechanism for NLRP3 or other inflammasome activation that is triggered by inactivity of Rho GTPases (81). …”

Section: Il-1-mediated Autoinflammatory Diseases (Group 1)mentioning

confidence: 99%

Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling

Jesús

Canna

Liu

et al. 2015

Annu. Rev. Immunol.

240

197

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Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.

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“…Low activity of MVK blocks the cholesterol biosynthetic pathway, resulting in shortage of nonsterol isoprenoids and decreased post-translational isoprenylation of selected proteins [37], such as small GTPases. Lack of prenylation can cause dysregulation of small GTPase activity and subcellular localization to membranes [38][39][40], resulting in defective autophagy and priming of the IL-1b response.…”

Section: Known Genetic Associationsmentioning

confidence: 99%

Mitochondria in autoinflammation: cause, mediator or bystander?

Burgh

Boes

2015

Trends in Endocrinology & Metabolism

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Unprenylated RhoA Contributes to IL-1β Hypersecretion in Mevalonate Kinase Deficiency Model through Stimulation of Rac1 Activity

Cited by 48 publications

References 38 publications

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling

Mitochondria in autoinflammation: cause, mediator or bystander?

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