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Nature Communications May 2023The bactericidal function of neutrophils is dependent on a myriad of intrinsic and extrinsic stimuli. Using systems immunology approaches we identify microbiome- and...
The bactericidal function of neutrophils is dependent on a myriad of intrinsic and extrinsic stimuli. Using systems immunology approaches we identify microbiome- and infection-induced changes in neutrophils. We focus on investigating the Prenylcysteine oxidase 1 like (Pcyox1l) protein function. Murine and human Pcyox1l proteins share ninety four percent aminoacid homology revealing significant evolutionary conservation and implicating Pcyox1l in mediating important biological functions. Here we show that the loss of Pcyox1l protein results in significant reductions in the mevalonate pathway impacting autophagy and cellular viability under homeostatic conditions. Concurrently, Pcyox1l CRISPRed-out neutrophils exhibit deficient bactericidal properties. Pcyox1l knock-out mice demonstrate significant susceptibility to infection with the gram-negative pathogen Psuedomonas aeruginosa exemplified through increased neutrophil infiltrates, hemorrhaging, and reduced bactericidal functionality. Cumulatively, we ascribe a function to Pcyox1l protein in modulation of the prenylation pathway and suggest connections beween metabolic responses and neutrophil functionality.
Topics: Animals; Humans; Mice; Mice, Knockout; Neutrophils; Oxidoreductases; Proteins
PubMed: 37179332
DOI: 10.1038/s41467-023-38447-z -
Cancer Metastasis Reviews Dec 2020KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies... (Review)
Review
KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies against mutant KRAS is urgently needed. One potential strategy involves disruption of K-Ras membrane localization, which is necessary for its proper function. In this review, we summarize the current data about the importance of membrane-anchorage of K-Ras and provide a critical evaluation of this targeting paradigm focusing mainly on prenylation inhibition. Additionally, we performed a RAS mutation-specific analysis of prenylation-related drug sensitivity data from a publicly available database ( https://depmap.org/repurposing/ ) of three classes of prenylation inhibitors: statins, N-bisphosphonates, and farnesyl-transferase inhibitors. We observed significant differences in sensitivity to N-bisphosphonates and farnesyl-transferase inhibitors depending on KRAS mutational status and tissue of origin. These observations emphasize the importance of factors affecting efficacy of prenylation inhibition, like distinct features of different KRAS mutations, tissue-specific mutational patterns, K-Ras turnover, and changes in regulation of prenylation process. Finally, we enlist the factors that might be responsible for the large discrepancy between the outcomes in preclinical and clinical studies including methodological pitfalls, the incomplete understanding of K-Ras protein turnover, and the variation of KRAS dependency in KRAS mutant tumors.
Topics: Animals; Antineoplastic Agents; Genes, ras; Humans; Molecular Targeted Therapy; Neoplasms; Prenylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras)
PubMed: 32524209
DOI: 10.1007/s10555-020-09902-w -
IUBMB Life Jan 2021Isoprenoids, also known as terpenes or terpenoids, represent a large family of natural products composed of five-carbon isopentenyl diphosphate or its isomer... (Review)
Review
Isoprenoids, also known as terpenes or terpenoids, represent a large family of natural products composed of five-carbon isopentenyl diphosphate or its isomer dimethylallyl diphosphate as the building blocks. Isoprenoids are structurally and functionally diverse and include dolichols, steroid hormones, carotenoids, retinoids, aromatic metabolites, the isoprenoid side-chain of ubiquinone, and isoprenoid attached signaling proteins. Productions of isoprenoids are catalyzed by a group of enzymes known as prenyltransferases, such as farnesyltransferases, geranylgeranyltransferases, terpenoid cyclase, squalene synthase, aromatic prenyltransferase, and cis- and trans-prenyltransferases. Because these enzymes are key in cellular processes and metabolic pathways, they are expected to be potential targets in new drug discovery. In this review, six distinct subsets of characterized prenyltransferases are structurally and mechanistically classified, including (1) head-to-tail prenyl synthase, (2) head-to-head prenyl synthase, (3) head-to-middle prenyl synthase, (4) terpenoid cyclase, (5) aromatic prenyltransferase, and (6) protein prenylation. Inhibitors of those enzymes for potential therapies against several diseases are discussed. Lastly, recent results on the structures of integral membrane enzyme, undecaprenyl pyrophosphate phosphatase, are also discussed.
Topics: Animals; Catalysis; Dimethylallyltranstransferase; Enzyme Inhibitors; Humans; Protein Conformation
PubMed: 33246356
DOI: 10.1002/iub.2418 -
Acta Pharmacologica Sinica Aug 2020Various lipids and lipid metabolites are bound to and modify the proteins in eukaryotic cells, which are known as 'protein lipidation'. There are four major types of the... (Review)
Review
Various lipids and lipid metabolites are bound to and modify the proteins in eukaryotic cells, which are known as 'protein lipidation'. There are four major types of the protein lipidation, i.e. myristoylation, palmitoylation, prenylation, and glycosylphosphatidylinositol anchor. N-myristoylation refers to the attachment of 14-carbon fatty acid myristates to the N-terminal glycine of proteins by N-myristoyltransferases (NMT) and affects their physiology such as plasma targeting, subcellular tracking and localization, thereby influencing the function of proteins. With more novel pathogenic N-myristoylated proteins are identified, the N-myristoylation will attract great attentions in various human diseases including infectious diseases, parasitic diseases, and cancers. In this review, we summarize the current understanding of N-myristoylation in physiological processes and discuss the hitherto implication of crosstalk between N-myristoylation and other protein modification. Furthermore, we mention several well-studied NMT inhibitors mainly in infectious diseases and cancers and generalize the relation of NMT and cancer progression by browsing the clinic database. This review also aims to highlight the further investigation into the dynamic crosstalk of N-myristoylation in physiological processes as well as the potential application of protein N-myristoylation in translational medicine.
Topics: Acyltransferases; Animals; Cell Biology; Enzyme Inhibitors; Humans; Lipoylation; Protein Processing, Post-Translational; Proteins; Signal Transduction; Translational Research, Biomedical
PubMed: 32203082
DOI: 10.1038/s41401-020-0388-4 -
Biochemical Pharmacology Aug 2018The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, ∼352 million... (Review)
Review
The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, ∼352 million individuals with impaired glucose tolerance are at increased risk for developing diabetes. Several mechanisms have been proposed for the onset of metabolic dysfunction and demise of the islet β-cell leading to the pathogenesis of diabetes. It is widely accepted that the onset of type 2 diabetes is due to an intricate interplay between genetic expression of the disease and a multitude of factors including increased oxidative and endoplasmic reticulum stress consequential to glucolipotoxicity and inflammation. Compelling experimental evidence from in vitro and in vivo studies implicates intracellular generation of ceramide (CER), a biologically-active sphingolipid, as a trigger in the onset of β-cell demise under above pathological conditions. Recent pharmacological and molecular biological evidence affirms regulatory roles for Ras-related C3 botulinum toxin substrate 1 (Rac1), a small G protein, in the islet β-cell function in health and diabetes. In this Commentary, we overviewed the emerging evidence implicating potential cross-talk between Rac1 and ceramide signaling pathways in the onset of metabolic dysregulation of the islet β-cell culminating in impaired physiological insulin secretion, loss of β-cell mass and the onset of diabetes. Further, we propose a model depicting contributory roles of defective protein lipidation (prenylation) pathway in the induction of metabolic defects in the β-cell under metabolic stress conditions. Potential avenues for the identification of novel therapeutic targets for the prevention/treatment of diabetes and its associated complications are highlighted.
Topics: Animals; Ceramides; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Oxidative Stress; Signal Transduction; rac1 GTP-Binding Protein
PubMed: 29715450
DOI: 10.1016/j.bcp.2018.04.026 -
Eukaryotic Cell Nov 2014Malaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid... (Review)
Review
Malaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.
Topics: Antimalarials; Fosfomycin; Malaria, Falciparum; Plasmodium falciparum; Terpenes
PubMed: 25217461
DOI: 10.1128/EC.00160-14 -
Cell Metabolism Dec 2020Effector regulatory T (eT) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling...
Effector regulatory T (eT) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling mechanisms that promote the differentiation and maintenance of eT cells remain unclear. Here, we show that isoprenoid-dependent posttranslational lipid modifications dictate eT cell accumulation and function by intersecting with TCR-induced intracellular signaling. We find that isoprenoids are essential for activated T cell suppressive activity, and T cell-specific deletion of the respective farnesylation- and geranylgeranylation-promoting enzymes Fntb or Pggt1b leads to the development of fatal autoimmunity, associated with reduced eT cell accumulation. Mechanistically, Fntb promotes eT cell maintenance by regulating mTORC1 activity and ICOS expression. In contrast, Pggt1b acts as a rheostat of TCR-dependent transcriptional programming and Rac-mediated signaling for establishment of eT cell differentiation and immune tolerance. Therefore, our results identify bidirectional metabolic signaling, specifically between immunoreceptor signaling and metabolism-mediated posttranslational lipid modifications, for the differentiation and maintenance of eT cells.
Topics: Animals; Cell Differentiation; Female; Immune Tolerance; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Prenylation; T-Lymphocytes, Regulatory; Terpenes
PubMed: 33207246
DOI: 10.1016/j.cmet.2020.10.022 -
Journal of Medicinal Chemistry Jul 2021A fundamental role of pancreatic β-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational... (Review)
Review
A fundamental role of pancreatic β-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational modifications, including prenylation. This covalent attachment with either a farnesyl or a geranylgeranyl group controls their localization, activity, and protein-protein interactions. Small GTPases are critical in maintaining glucose homeostasis acting in the pancreas and metabolically active tissues such as skeletal muscles, liver, or adipocytes. Hyperglycemia-induced upregulation of small GTPases suggests that inhibition of these pathways deserves to be considered as a potential therapeutic approach in treating T2D. This Perspective presents how inhibition of various points in the mevalonate pathway might affect protein prenylation and functioning of diabetes-affected tissues and contribute to chronic inflammation involved in diabetes mellitus (T2D) development. We also demonstrate the currently available molecular tools to decipher the mechanisms linking the mevalonate pathway's enzymes and GTPases with diabetes.
Topics: Animals; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Molecular Structure; Monomeric GTP-Binding Proteins; Structure-Activity Relationship
PubMed: 34236862
DOI: 10.1021/acs.jmedchem.1c00410 -
Molecular & Cellular Proteomics : MCP Aug 2023Proteins containing a CAAX motif at the C-terminus undergo prenylation for localization and activity and include a series of key regulatory proteins, such as RAS...
Proteins containing a CAAX motif at the C-terminus undergo prenylation for localization and activity and include a series of key regulatory proteins, such as RAS superfamily members, heterotrimeric G proteins, nuclear lamina protein, and several protein kinases and phosphatases. However, studies of prenylated proteins in esophageal cancer are limited. Here, through research on large-scale proteomic data of esophageal cancer in our laboratory, we found that paralemmin-2 (PALM2), a potential prenylated protein, was upregulated and associated with poor prognosis in patients. Low-throughput verification showed that the expression of PALM2 in esophageal cancer tissues was higher than that in their paired normal esophageal epithelial tissues, and it was generally expressed in the membrane and cytoplasm of esophageal cancer cells. PALM2 interacted with the two subunits of farnesyl transferase (FTase), FNTA and FNTB. Either the addition of an FTase inhibitor or mutation in the CAAX motif of PALM2 (PALM2) impaired its membranous localization and reduced the membrane location of PALM2, indicating PALM2 was prenylated by FTase. Overexpression of PALM2 enhanced the migration of esophageal squamous cell carcinoma cells, whereas PALM2 lost this ability. Mechanistically, PALM2 interacted with the N-terminal FERM domain of ezrin of the ezrin/radixin/moesin (ERM) family. Mutagenesis indicated that lysine residues K253/K254/K262/K263 in ezrin's FERM domain and C408 in PALM2's CAAX motif were important for PALM2/ezrin interaction and ezrin activation. Knockout of ezrin prevented enhanced cancer cell migration by PALM2 overexpression. PALM2, depending on its prenylation, increased both ezrin membrane localization and phosphorylation of ezrin at Y146. In summary, prenylated PALM2 enhances the migration of cancer cells by activating ezrin.
Topics: Humans; Cell Movement; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Proteomics
PubMed: 37328063
DOI: 10.1016/j.mcpro.2023.100593 -
RSC Medicinal Chemistry Jan 2020Protein prenylation is a critical mediator in several diseases including cancer and acquired immunodeficiency syndrome (AIDS). Therapeutic intervention has focused... (Review)
Review
Protein prenylation is a critical mediator in several diseases including cancer and acquired immunodeficiency syndrome (AIDS). Therapeutic intervention has focused primarily on directly targeting the prenyltransferase enzymes, FTase and GGTase I and II. To date, several drugs have advanced to clinical trials and while promising, they have yet to gain approval in a medical setting due to off-target effects and compensatory mechanisms activated by the body which results in drug resistance. While the development of dual inhibitors has mitigated undesirable side effects, potency remains sub-optimal for clinical development. An alternative approach involves antagonizing the upstream mevalonate pathway enzymes, FPPS and GGPPS, which mediate prenylation as well as cholesterol synthesis. The development of these inhibitors presents novel opportunities for dual inhibition of cancer-driven prenylation as well as cholesterol accumulation. Herein, we highlight progress towards the development of inhibitors against the prenylation machinery.
PubMed: 33479604
DOI: 10.1039/c9md00442d