نتائج البحث - "Protein prenylation"

71

Atorvastatin disrupts primary human brain microvascular endothelial cell functions via prenylation‐dependent mitochondrial inhibition and oxidative stress

المؤلفون: Qian Tan, Danfang Yu, Lin Song

المصدر: Fundamental & Clinical Pharmacology. 35:341-350

مصطلحات موضوعية: Angiogenesis, Atorvastatin, Pharmacology, medicine.disease_cause, 030226 pharmacology & pharmacy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Prenylation, health services administration, medicine, Humans, heterocyclic compounds, Pharmacology (medical), cardiovascular diseases, Cell adhesion, Anticholesteremic Agents, Endothelial Cells, nutritional and metabolic diseases, Endothelial stem cell, Vascular endothelial growth factor, chemistry, Blood-Brain Barrier, Protein prenylation, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, 030217 neurology & neurosurgery, Oxidative stress, medicine.drug

الوصف: Primary human brain microvascular endothelial cell (HBMEC) is the major component of the blood-brain barrier (BBB). Atorvastatin, a HMG-CoA reductase inhibitor, is a cholesterol-lowering drug commonly used to reduce the risk for cardiovascular disease. Numerous studies have reported the pleiotropic effects of atorvastatin on endothelial cells, but the findings are controversial and inconclusive. In addition, little is known about the biological effects of atorvastatin on HBMEC. In this work, we demonstrate that atorvastatin at micromolar but not nanomolar concentrations induces dysfunctions of a number of HBMEC events, including differentiation into capillary network, migration and growth but not cell adhesion. We further show that the inhibitory effects of atorvastatin on HBMEC are independent of angiogenesis stimulators. Atorvastatin induces HBMEC apoptosis even in the presence of vascular endothelial growth factor (VEGF) and serum. Mechanism studies indicate that atorvastatin at micromolar concentration leads to protein prenylation inhibition, mitochondrial dysfunction and thereby subsequent oxidative stress and damage in HBMEC. Rescue experiments confirm that atorvastatin inhibits HBMEC functions via prenylation-dependent mitochondrial inhibition. Our work reveals the inhibitory effects of atorvastatin on HBMEC and suggests the possible negative influence of atorvastatin in blood-brain barrier.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6180a8db4bdf7c3fac8768a7265acb29Test
https://doi.org/10.1111/fcp.12615Test

72

Glycolysis and subsequent mevalonate biosynthesis play an important role in Th2 cell differentiation

المؤلفون: Yasushi Imai, Junpei Suzuki, Makoto Kuwahara, Masakatsu Yamashita, Yuichiro Yagi

المصدر: Biochemical and Biophysical Research Communications. 530:355-361

الوصف: Th2 cytokine such as IL-4, IL -5 and IL-13 are important therapeutic targets for Th2-type chronic inflammation. Several biologics targeting Th2 cytokine and its receptors are effective in clinical practice; however, the development of small-molecule compounds that inhibit Th2 cytokine productions is awaited. We found that an inhibitor for pyruvate dehydrogenase kinase (PDHK) suppresses the differentiation of IL-5/IL-13-producing Th2 cells. The expression of the Th2-related transcriptional factors Pparγ was decreased by treatment with inhibitor, whereas Gata3, a master regulator of Th2 cell differentiation, remained unchanged. The oxygen consumption rate was unaffected, whereas the level of farnesylated proteins was decreased by the PDHK inhibitor. Furthermore, the inhibitors for farnesyltransferase and hydroxymethylglutaryl-CoA reductase showed an inhibitory effect similar to that of the PDHK inhibitor. These results suggest that the mevalonate biosynthesis and subsequent protein prenylation may be novel therapeutic target for Th2 cell-dependent immune dysregulation, such as in allergic diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::83c56cee89268f5ada4e30aa089e3c47Test
https://doi.org/10.1016/j.bbrc.2020.08.009Test

73

The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis

المؤلفون: Maria Laura Gennaro, Petros C. Karakousis, Valentina Guerrini, Hugh Salamon, Natalie Bruiners, Ken D. Yamaguchi, Noton K. Dutta

المصدر: Journal of Lipid Research
Journal of Lipid Research, Vol 61, Iss 12, Pp 1617-1628 (2020)

مصطلحات موضوعية: 0301 basic medicine, Simvastatin, Antitubercular Agents, mechanistic target of rapamycin complex 1 regulation, mTORC1, QD415-436, 030204 cardiovascular system & hematology, Pharmacology, AMP-Activated Protein Kinases, Mechanistic Target of Rapamycin Complex 1, Biochemistry, statins, lipids, immunology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Prenylation, adenosine 5′-monophosphate-activated protein kinase-mechanistic target of rapamycin complex 1-transcription factor EB axis, medicine, Autophagy, Animals, Humans, Phosphorylation, Research Articles, Chemistry, Cholesterol, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Macrophages, AMPK, Cell Biology, Mycobacterium tuberculosis, macrophages/monocytes, 030104 developmental biology, Protein prenylation, TFEB, lipids (amino acids, peptides, and proteins), Mevalonate pathway, Lysosomes, medicine.drug, Signal Transduction

الوصف: The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin's anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9ea347c241b93f33c3bce3f2b688746fTest
http://europepmc.org/articles/PMC7707180Test

74

Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency

المصدر: Journal of Clinical Investigation, 132
Journal of Clinical Investigation, 132, 19

مصطلحات موضوعية: Lipopolysaccharides, Fever, Inflammasomes, Protein Prenylation, Mevalonic Acid, General Medicine, Body Temperature, GTP Phosphohydrolases, Mice, Phosphotransferases (Alcohol Group Acceptor), NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Humans, Mevalonate Kinase Deficiency, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]

الوصف: Contains fulltext : 286880.pdf (Publisher’s version ) (Open Access) Mevalonate kinase deficiency (MKD) is characterized by recurrent fevers and flares of systemic inflammation, caused by biallelic loss-of-function mutations in MVK. The underlying disease mechanisms and triggers of inflammatory flares are poorly understood because of the lack of in vivo models. We describe genetically modified mice bearing the hypomorphic mutation p.Val377Ile (the commonest variant in patients with MKD) and amorphic, frameshift mutations in Mvk. Compound heterozygous mice recapitulated the characteristic biochemical phenotype of MKD, with increased plasma mevalonic acid and clear buildup of unprenylated GTPases in PBMCs, splenocytes, and bone marrow. The inflammatory response to LPS was enhanced in compound heterozygous mice and treatment with the NLRP3 inflammasome inhibitor MCC950 prevented the elevation of circulating IL-1β, thus identifying a potential inflammasome target for future therapeutic approaches. Furthermore, lines of mice with a range of deficiencies in mevalonate kinase and abnormal prenylation mirrored the genotype-phenotype relationship in human MKD. Importantly, these mice allowed the determination of a threshold level of residual enzyme activity, below which protein prenylation is impaired. Elevated temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and the defective prenylation in vitro and in vivo, highlighting increased body temperature as a likely trigger of inflammatory flares.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d88af00df37878b418362b627a4d80b8Test
https://hdl.handle.net/2066/286880Test

75

Inhibition of the miR-155 and protein prenylation feedback loop alleviated acute graft-versus-host disease through regulating the balance between T helper 17 and Treg cells

المؤلفون: Xiaoxiao Wang, Qiuling Wu, Zhenli Huang, Sibin Zang, Linghui Xia, Ran Zhang

المصدر: Transplant immunology. 69

الوصف: MicroRNA-155(miR-155) and protein prenylation have been reported to participate in acute graft-versus-host disease (aGVHD) through modulating T lymphocyte differentiation, however the mechanism remains elusive. In this study, we found that the expression of miR-155 and protein prenyltransferases in peripheral blood T lymphocytes of aGVHD mice was significantly increased. Suppression of miR-155 by antagomir-155 could remarkably reduce prenyltransferases mRNA and protein expression in T lymphocytes of aGVHD mice. Conversely, prenyltransferase inhibitors significantly reduced the level of miR-155. Inhibition of this feedback loop of miR-155 and protein prenylation in aGVHD mice led to improved survival and lower aGVHD histopathology scores and significantly induced T cell deficient differentiation towards T helper 17 (Th17) cells and titled differentiation towards CD4+CD25hi regulatory T (Treg) cells. Furthermore, the immunoregulatory effects and protection from aGVHD of prenyltransferase inhibitors could be reversed by the addition of miR-155. The dual treatment of prenylation inhibitors and antagomir-155 showed synergistic effects on T polarization and protection from aGVHD. Consistent with the in vivo changes, inhibition of this feedback loop of miR-155 and protein prenylation affected Th17 and Treg cell polarization in vitro. Our data suggest that miR-155 and protein prenylation may constitute a feedback loop that amplifies immune and inflammatory responses in subjects with aGVHD, and they may serve as potential targets for aGVHD prophylaxis and treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::54cd607a6199b9e088ff7314be695917Test
https://pubmed.ncbi.nlm.nih.gov/34487810Test

76

Metabolic labeling with an alkyne probe reveals similarities and differences in the prenylomes of several brain-derived cell lines and primary cells

المؤلفون: Kiall F. Suazo, Ling Li, Mark D. Distefano, Angela Jeong, Caroline Brown, Mina Ahmadi, Wenhui Qu

المصدر: Scientific Reports
Scientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)

مصطلحات موضوعية: Proteomics, Proteome, Science, Cell, Protein Prenylation, Mass Spectrometry, Article, Mice, Prenylation, Chlorocebus aethiops, medicine, Animals, Humans, Primary cell, Cells, Cultured, Neurons, Multidisciplinary, Microglia, Chemistry, Brain, Lipids, Cell biology, Mice, Inbred C57BL, medicine.anatomical_structure, Cell culture, Alkynes, Astrocytes, COS Cells, Medicine, Protein prenylation, Signal transduction, Chemical tools, HeLa Cells, Cysteine

الوصف: Protein prenylation involves the attachment of one or two isoprenoid group(s) onto cysteine residues positioned near the C-terminus. This modification is essential for many signal transduction processes. In this work, the use of the probe C15AlkOPP for metabolic labeling and identification of prenylated proteins in a variety of cell lines and primary cells is explored. Using a single isoprenoid analogue, 78 prenylated protein groups from the three classes of prenylation substrates were identified including three novel prenylation substrates in a single experiment. Applying this method to three brain-related cell lines including neurons, microglia, and astrocytes showed substantial overlap (25%) in the prenylated proteins identified. In addition, some unique prenylated proteins were identified in each type. Eight proteins were observed exclusively in neurons, five were observed exclusively in astrocytes and three were observed exclusively in microglia, suggesting their unique roles in these cells. Furthermore, inhibition of farnesylation in primary astrocytes revealed the differential responses of farnesylated proteins to an FTI. Importantly, these results provide a list of 19 prenylated proteins common to all the cell lines studied here that can be monitored using the C15AlkOPP probe as well as a number of proteins that were observed in only certain cell lines. Taken together, these results suggest that this chemical proteomic approach should be useful in monitoring the levels and exploring the underlying role(s) of prenylated proteins in various diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::127e802e0ebeb3e60e8c0411b32d36b4Test
https://doi.org/10.1038/s41598-021-83666-3Test

77

Prenylated quinolinecarboxylic acid compound-18 prevents sensory nerve fiber outgrowth through inhibition of the interleukin-31 pathway

المؤلفون: Masato Ogura, Kumiko Endo, Toshiyuki Suzuki, Yoshimi Homma

المصدر: PLoS ONE
PLoS ONE, Vol 16, Iss 2, p e0246630 (2021)

مصطلحات موضوعية: Male, Cancer Treatment, Carboxylic Acids, Social Sciences, Biochemistry, Ointments, Mice, Nerve Fibers, Dorsal root ganglion, Animal Cells, Ganglia, Spinal, Medicine and Health Sciences, Psychology, Post-Translational Modification, Phosphorylation, STAT3, Topical Medications, Skin, Neurons, Multidisciplinary, Janus kinase 2, biology, Kinase, Chemistry, Applied Mathematics, Cutaneous nerve, Drugs, Cell Differentiation, Cell biology, Precipitation Techniques, medicine.anatomical_structure, Oncology, Quinolines, Medicine, Sensory Perception, Cellular Types, Sensory nerve, Research Article, Signal Transduction, STAT3 Transcription Factor, Neurite, Sensory Receptor Cells, General Mathematics, Science, Immunology, Protein Prenylation, Research and Analysis Methods, Dermatitis, Atopic, Antibody Therapy, Peripheral Nervous System, medicine, Neurites, Immunoprecipitation, Animals, Nerve Growth Factors, Pharmacology, Pruritus, Interleukins, Cognitive Psychology, Biology and Life Sciences, Proteins, Cell Biology, Neuronal Dendrites, Janus Kinase 2, Mice, Inbred C57BL, p21-Activated Kinases, Cellular Neuroscience, biology.protein, STAT protein, Protein prenylation, Cognitive Science, Perception, Clinical Immunology, Clinical Medicine, Neuroscience

الوصف: Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::add3c38cb73a9487a001e54fba228248Test
http://europepmc.org/articles/PMC7861556Test

78

Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages

المؤلفون: Marcia A Munoz, Emma K Fletcher, Oliver P Skinner, Julie Jurczyluk, Esther Kristianto, Mark P Hodson, Shuting Sun, Frank H Ebetino, David R Croucher, Philip M Hansbro, Jacqueline R Center, Michael J Rogers

المصدر: eLife
eLife, Vol 10 (2021)

الوصف: Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.

وصف الملف: Electronic; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b652d1f6ff12367a2fb7e955fbcebc41Test
https://doi.org/10.7554/elife.72430Test

79

Bacteria Are New Targets for Inhibitors of Human Farnesyltransferase

المؤلفون: Jila Kaltenhäuser, Ewa Klara Stuermer, Anja Ehrhardt, Patrick Rockenfeller, Manuela Besser, Lea Weber, Hagen S. Bachmann, Anna Hagemann

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

الوصف: Farnesyltransferase inhibitors (FTIs) are focus for the treatment of several diseases, particularly in the field of cancer therapy. Their potential, however, goes even further, as a number of studies have evaluated FTIs for the treatment of infectious diseases such as malaria, African sleeping sickness, leishmaniosis, and hepatitis D virus infection. Little is known about protein prenylation mechanisms in human pathogens. However, disruption of IspA, a gene encoding the geranyltranstransferase of Staphylococcus aureus (S. aureus) leads to reprogramming of cellular behavior as well as impaired growth and decreased resistance to cell wall-targeting antibiotics. We used an agar well diffusion assay and a time kill assay and determined the minimum inhibitory concentrations of the FTIs lonafarnib and tipifarnib. Additionally, we conducted cell viability assays. We aimed to characterize the effect of these FTIs on S. aureus, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (S. epidermidis), Escherichia coli (E. coli), Enterococcus faecium (E. faecium), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa), and Streptococcus pneumoniae (S. pneumoniae). Both the FTIs lonafarnib and tipifarnib were capable of inhibiting the growth of the Gram-positive bacteria S. aureus, MRSA, S. epidermidis, and S. pneumoniae, whereas no effect was observed on Gram-negative bacteria. The analysis of the impact of lonafarnib and tipifarnib on common human pathogens might lead to novel insights into their defense mechanisms and therefore provide new therapeutic targets for antibiotic-resistant bacterial infections.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5f5fe51d6b6e5f11fa2406314f392c4aTest
https://doi.org/10.3389/fmicb.2021.628283Test

80

GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase

المؤلفون: Antonio Marzio, Mark R. Philips, Michele Pagano, Shafi Kuchay, Kunj Jain, Nicole Fehrenbacher, Harrison Homer, Hui Wang, Ning Zheng

المصدر: Nature structural & molecular biology

الوصف: Protein prenylation is believed to be catalyzed by three heterodimeric enzymes: FTase, GGTase1 and GGTase2. Here we report the identification of a previously unknown human prenyltransferase complex consisting of an orphan prenyltransferase α-subunit, PTAR1, and the catalytic β-subunit of GGTase2, RabGGTB. This enzyme, which we named GGTase3, geranylgeranylates FBXL2 to allow its localization at cell membranes, where this ubiquitin ligase mediates the polyubiquitylation of membrane-anchored proteins. In cells, FBXL2 is specifically recognized by GGTase3 despite having a typical carboxy-terminal CaaX prenylation motif that is predicted to be recognized by GGTase1. Our crystal structure analysis of the full-length GGTase3-FBXL2-SKP1 complex reveals an extensive multivalent interface specifically formed between the leucine-rich repeat domain of FBXL2 and PTAR1, which unmasks the structural basis of the substrate-enzyme specificity. By uncovering a missing prenyltransferase and its unique mode of substrate recognition, our findings call for a revision of the 'prenylation code'.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2694ef572e7d623f73f93b496ae51d5bTest
https://doi.org/10.1038/s41594-019-0249-3Test

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