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Molecular Neurobiology Mar 2021Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic...
Protein prenylation is a post-translational lipid modification that governs a variety of important cellular signaling pathways, including those regulating synaptic functions and cognition in the nervous system. Two enzymes, farnesyltransferase (FT) and geranylgeranyltransferase type I (GGT), are essential for the prenylation process. Genetic reduction of FT or GGT ameliorates neuropathology but only FT haplodeficiency rescues cognitive function in transgenic mice of Alzheimer's disease. A follow-up study showed that systemic or forebrain neuron-specific deficiency of GGT leads to synaptic and cognitive deficits under physiological conditions. Whether FT plays different roles in shaping neuronal functions and cognition remains elusive. This study shows that in contrast to the detrimental effects of GGT reduction, systemic haplodeficiency of FT has little to no impact on hippocampal synaptic plasticity and cognition. However, forebrain neuron-specific FT deletion also leads to reduced synaptic plasticity, memory retention, and hippocampal dendritic spine density. Furthermore, a novel prenylomic analysis identifies distinct pools of prenylated proteins that are affected in the brain of forebrain neuron-specific FT and GGT knockout mice, respectively. Taken together, this study uncovers that physiological levels of FT and GGT in neurons are essential for normal synaptic/cognitive functions and that the prenylation status of specific signaling molecules regulates neuronal functions.
Topics: Alkyl and Aryl Transferases; Animals; Cognition; Dendritic Spines; Hippocampus; Long-Term Potentiation; Maze Learning; Mice; Neuronal Plasticity; Neurons; Protein Prenylation; Spatial Learning; Spatial Memory; Synapses
PubMed: 33098528
DOI: 10.1007/s12035-020-02169-w -
Biomolecules Aug 2020Structurally diverse carbazole alkaloids are valuable due to their pharmaceutical properties and have been isolated from nature. Experimental knowledge on carbazole... (Review)
Review
Structurally diverse carbazole alkaloids are valuable due to their pharmaceutical properties and have been isolated from nature. Experimental knowledge on carbazole biosynthesis is limited. The latest development of in silico analysis of the biosynthetic gene clusters for bacterial carbazoles has allowed studies on the biosynthesis of a carbazole skeleton, which was established by sequential enzyme-coupling reactions associated with an unprecedented carbazole synthase, a thiamine-dependent enzyme, and a ketosynthase-like enzyme. This review describes the carbazole biosynthetic mechanism, which includes a key step in enzymatic formation of a tricyclic carbazole skeleton, followed by modifications such as prenylation and hydroxylation in the skeleton.
Topics: Actinobacteria; Bacterial Proteins; Carbazoles
PubMed: 32764478
DOI: 10.3390/biom10081147 -
Respiratory Research Dec 2022Chronic obstructive pulmonary disease (COPD) is a progressive disorder that causes airway obstruction and lung inflammation. The first-line treatment of COPD is the...
Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a progressive disorder that causes airway obstruction and lung inflammation. The first-line treatment of COPD is the bronchodilators of β2-agonists and antimuscarinic drugs, which can help control the airway obstruction, but the long-term use might render the drug tolerance. Bisphosphonates are widely used in osteoclast-mediated bone diseases treatment for decades. For drug repurposing, can delivery of a third generation of nitrogen-containing bisphosphonate, risedronate (RIS) ameliorate the progression of COPD?
METHODS
COPD rats or mice models have been established through cigarette-smoking and elastase injection, and then the animals are received RIS treatment via nebulization. Lung deposition of RIS was primarily assessed by high-performance liquid chromatography (HPLC). The respiratory parameters of airway obstruction in COPD rats and mice were documented using plethysmography method and resistance-compliance system.
RESULTS
High lung deposition and bioavailability of RIS was monitored with 88.8% of RIS input dose. We found that RIS could rescue the lung function decline of airspace enlargement and mean linear intercept in the COPD lung. RIS could curb the airway obstruction by suppressing 60% of the respiratory resistance and elevating the airway's dynamic compliance, tidal volume and mid-expiratory flow. As an inhibitor of farnesyl diphosphate synthase (FDPS), RIS suppresses FDPS-mediated RAS and RhoA prenylation to obstruct its membrane localization in airway smooth muscle cells (ASMCs), leading to the inhibition of downstream ERK-MLCK and ROCK1-MLCP pathway to cause ASMCs relaxation. Additionally, RIS nebulization impeded pro-inflammatory cell accumulation, particularly macrophages infiltration in alveolar parenchyma. The NF-κB, tumor necrosis factor-alpha, IL-1β, IL-8, and IL-6 declined in microphages following RIS nebulization. Surprisingly, nebulization of RIS could overcome the tolerance of β2-agonists in COPD-rats by increasing the expression of β2 receptors.
CONCLUSIONS
Nebulization of RIS could alleviate airway obstruction and lung inflammation in COPD, providing a novel strategy for treating COPD patients, even those with β2-agonists tolerance.
Topics: Rats; Mice; Animals; NF-kappa B; Risedronic Acid; Pulmonary Disease, Chronic Obstructive; Lung; Airway Obstruction; Inflammation; Prenylation; rho-Associated Kinases
PubMed: 36575527
DOI: 10.1186/s12931-022-02274-5 -
Science Translational Medicine Jul 2021Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome...
Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; ) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.
Topics: Animals; Dopamine; Mice; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Prenylation; Repressor Proteins; Substantia Nigra
PubMed: 34321320
DOI: 10.1126/scitranslmed.aax8891 -
Journal of Biochemistry Apr 2021Ykt6 is an evolutionarily conserved SNARE protein regulating Golgi membrane fusion and other diverse membrane trafficking pathways. Unlike most SNARE proteins, Ykt6...
Ykt6 is an evolutionarily conserved SNARE protein regulating Golgi membrane fusion and other diverse membrane trafficking pathways. Unlike most SNARE proteins, Ykt6 lacks a transmembrane domain but instead has a tandem cysteine motif at the C-terminus. Recently, we have demonstrated that Ykt6 undergoes double prenylation at the C-terminal two cysteines first by farnesyltransferase and then by a newly identified protein prenyltransferase named geranylgeranyltransferase type-III (GGTase-III). GGTase-III consists of a novel α subunit prenyltransferase alpha subunit repeat containing 1 (PTAR1) and the β subunit of Rab geranylgeranyltransferase. PTAR1 knockout (KO) cells, where Ykt6 is singly prenylated with a farnesyl moiety, exhibit structural and functional abnormalities in the Golgi apparatus with delayed intra-Golgi trafficking and impaired protein glycosylation. It remains unclear whether the second prenylation of Ykt6 is required for proper trafficking of lysosomal hydrolases from Golgi to lysosomes. Here, we show that lysosomal hydrolases, cathepsin D and β-hexosaminidase, were missorted at the trans-Golgi network and secreted into the extracellular space in PTAR1 KO cells. Moreover, maturation of these hydrolases was disturbed. LC3B, an autophagy marker, was accumulated in PTAR1 KO cells, suggesting defects in cellular degradation pathways. Thus, doubly prenylated Ykt6, but not singly prenylated Ykt6, is critical for the efficient sorting and trafficking of acid hydrolases to lysosomes.
Topics: Alkyl and Aryl Transferases; Animals; Dimethylallyltranstransferase; Golgi Apparatus; HeLa Cells; Humans; Hydrolases; Lysosomes; Membrane Fusion; Protein Prenylation; Protein Transport; R-SNARE Proteins; SNARE Proteins
PubMed: 33035318
DOI: 10.1093/jb/mvaa111 -
CaaX-motif-adjacent residues influence G protein gamma (Gγ) prenylation under suboptimal conditions.The Journal of Biological Chemistry Nov 2023Prenylation is an irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including...
Prenylation is an irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including migration, proliferation, and survival. Dysregulation of prenylation contributes to multiple disorders, including cancers and vascular and neurodegenerative diseases. Prenyltransferases tether isoprenoid lipids to proteins via a thioether linkage during prenylation. Pharmacological inhibition of the lipid synthesis pathway by statins is a therapeutic approach to control hyperlipidemia. Building on our previous finding that statins inhibit membrane association of G protein γ (Gγ) in a subtype-dependent manner, we investigated the molecular reasoning for this differential inhibition. We examined the prenylation of carboxy-terminus (Ct) mutated Gγ in cells exposed to Fluvastatin and prenyl transferase inhibitors and monitored the subcellular localization of fluorescently tagged Gγ subunits and their mutants using live-cell confocal imaging. Reversible optogenetic unmasking-masking of Ct residues was used to probe their contribution to prenylation and membrane interactions of the prenylated proteins. Our findings suggest that specific Ct residues regulate membrane interactions of the Gγ polypeptide, statin sensitivity, and extent of prenylation. Our results also show a few hydrophobic and charged residues at the Ct are crucial determinants of a protein's prenylation ability, especially under suboptimal conditions. Given the cell and tissue-specific expression of different Gγ subtypes, our findings indicate a plausible mechanism allowing for statins to differentially perturb heterotrimeric G protein signaling in cells depending on their Gγ-subtype composition. Our results may also provide molecular reasoning for repurposing statins as Ras oncogene inhibitors and the failure of using prenyltransferase inhibitors in cancer treatment.
Topics: Humans; Amino Acid Motifs; Drug Resistance; HeLa Cells; Heterotrimeric GTP-Binding Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Molecular; Mutation; Protein Prenylation; Protein Structure, Tertiary; Protein Transport; Signal Transduction
PubMed: 37739036
DOI: 10.1016/j.jbc.2023.105269 -
Frontiers in Oncology 2019Tumor metastasis is a sequential event accounting for numerous cancer-related fatalities worldwide. The process of metastasis serially involves invasion, intravasation,... (Review)
Review
Tumor metastasis is a sequential event accounting for numerous cancer-related fatalities worldwide. The process of metastasis serially involves invasion, intravasation, extravasation, and tumor growth at the secondary site. Migration and invasion enhancer 1 (MIEN1) is a membrane associated protein overexpressed in various human cancers. Biological activity of MIEN1 is driven by geranylgeranyltransferase-I mediated prenylation at CAAX motif and methylation of the prenylated protein that anchors MIEN1 into the cellular membrane. Post-translationally modified MIEN1 interacts with Syk kinase and Annexin A2 protein; polymerizes G-actin and stabilizes F-actin filament; induces focal adhesion kinase phosphorylation and decrease cofilin phosphorylation implicated in both invasion and metastasis of different cancer types. In the present review, we discuss the structure, function, and involvement of MIEN1 in cancer progression. We also highlight the future prospects of MIEN1 as an emerging molecule and novel target in cancer cell invasion and metastasis.
PubMed: 31552186
DOI: 10.3389/fonc.2019.00868 -
Transplant Immunology Dec 2021MicroRNA-155(miR-155) and protein prenylation have been reported to participate in acute graft-versus-host disease (aGVHD) through modulating T lymphocyte...
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.
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 CD4CD25 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.
Topics: Acute Disease; Animals; Feedback; Graft vs Host Disease; Mice; Mice, Inbred C57BL; MicroRNAs; Protein Prenylation; T-Lymphocytes, Regulatory
PubMed: 34487810
DOI: 10.1016/j.trim.2021.101461 -
Journal of Molecular and Cellular... Jan 2020Cardiovascular disease (CVD) is one of the most threatening diseases to human health and life, and the number of patients is increasing year by year. Thus, it is of... (Review)
Review
Cardiovascular disease (CVD) is one of the most threatening diseases to human health and life, and the number of patients is increasing year by year. Thus, it is of great significance to study the pathogenesis, prevention and treatment of CVDs. The occurrence and development of CVDs involve dynamic, complex and delicate intracellular processes and the pathogenesis is not entirely clear. In contrast to genetic mutations, most of the protein post-translational modifications (PTMs) are reversible, and can affect the activity, stability, subcellular localization, protein-protein interaction etc., of the substrate targets, emerging as key mediators of a number of CVD progression. Under pathological conditions, the PTMs undergo aberrant balances which cause changes of the substrate target proteins in expression level, localization and capacity to activate downstream signaling pathways. Therefore, new approaches can be created aiming to correct the abnormal PTM alterations in treating CVDs. This review summarizes some of the more recent advances in PTMs, focusing on SUMOylation, neddylation, succinylation, and prenylation, and the effect of these modifications on cardiovascular function and progression, which may provide potential targets for future therapeutics.
Topics: Animals; Cardiovascular Diseases; Humans; Prenylation; Protein Processing, Post-Translational; Succinic Acid; Sumoylation; Ubiquitination
PubMed: 31751566
DOI: 10.1016/j.yjmcc.2019.11.146 -
The Journal of Pathology Mar 2022Investigations of major mevalonate pathway enzymes have demonstrated the importance of local isoprenoid synthesis in cardiac homeostasis. Farnesyl diphosphate synthase...
Investigations of major mevalonate pathway enzymes have demonstrated the importance of local isoprenoid synthesis in cardiac homeostasis. Farnesyl diphosphate synthase (FPPS) synthesizes isoprenoid precursors needed for cholesterol biosynthesis and protein prenylation. Wang, Zhang, Chen et al, in a recently published article in The Journal of Pathology, elegantly elucidated the pathological outcomes of FPPS deficiency in cardiomyocytes, which paradoxically resulted in increased prenylation of the small GTPases Ras and Rheb. Cardiomyocyte FPPS depletion caused severe dilated cardiomyopathy that was associated with enhanced GTP-loading and abundance of Ras and Rheb in lipidated protein-enriched cardiac fractions and robust activation of downstream hypertrophic ERK1/2 and mTOR signaling pathways. Cardiomyopathy and activation of ERK1/2 and mTOR caused by loss of FPPS were ameliorated by inhibition of farnesyltransferase, suggesting that impairment of FPPS activity results in promiscuous activation of Ras and Rheb through non-canonical actions of farnesyltransferase. Here, we discuss the findings and adaptive signaling mechanisms in response to disruption of local cardiomyocyte mevalonate pathway activity, highlighting how alteration in a key branch point in the mevalonate pathway affects cardiac biology and function and perturbs protein prenylation, which might unveil novel strategies and intricacies of targeting the mevalonate pathway to treat cardiovascular diseases. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Heart Failure; Humans; Mevalonic Acid; Monomeric GTP-Binding Proteins; Myocytes, Cardiac; Prenylation; Protein Prenylation
PubMed: 34783037
DOI: 10.1002/path.5837