-
Nature Reviews. Immunology May 2006Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that... (Review)
Review
Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that statins also have extensive immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therapeutic agents for the treatment of autoimmune disease. Modulation of post-translational protein prenylation seems to be a key mechanism by which statins alter immune function. In this Review, the effect of statin therapy on immune function, and how this relates to the pathogenesis of autoimmune disease, is reviewed alongside current opinion of what the key biological targets of statins are.
Topics: Animals; Autoimmune Diseases; Drug Delivery Systems; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunologic Factors; Protein Prenylation
PubMed: 16639429
DOI: 10.1038/nri1839 -
Biochemical Society Transactions Feb 2013The study of post-translational modifications such as protein lipidation is a non-trivial challenge of the post-genomic era. In recent years the field of chemical... (Review)
Review
The study of post-translational modifications such as protein lipidation is a non-trivial challenge of the post-genomic era. In recent years the field of chemical proteomics has greatly advanced our ability to identify and quantify protein lipidation. In the present review, we give a brief overview of the tools available to study protein acylation, prenylation and cholesterylation, and their application in the identification and quantification of protein lipidation in health and disease.
Topics: Acylation; Cholesterol; Lipids; Lipoylation; Models, Molecular; Molecular Probes; Myristic Acid; Palmitic Acid; Protein Prenylation; Proteins; Proteomics
PubMed: 23356258
DOI: 10.1042/BST20120283 -
Journal of Internal Medicine Aug 2020The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are... (Review)
Review
The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are found in most pancreatic, half of colorectal and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. Consequently, KRAS has been the subject of exhaustive drug-targeting efforts over the past 3-4 decades. These efforts have included targeting the KRAS protein itself but also its posttranslational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. Most of these strategies have failed and no KRAS-specific drugs have yet been approved. However, for one specific mutation, KRAS , there is light on the horizon. MRTX849 was recently identified as a potent, selective and covalent KRAS inhibitor that possesses favourable drug-like properties. MRTX849 selectively modifies the mutant cysteine residue in GDP-bound KRAS and inhibits GTP-loading and downstream KRAS-dependent signalling. The drug inhibits the in vivo growth of multiple KRAS -mutant cell line xenografts, causes tumour regression in patient-derived xenograft models and shows striking responses in combination with other agents. It has also produced objective responses in patients with mutant-specific lung and colorectal cancer. In this review, we discuss the history of RAS drug-targeting efforts, the discovery of MRTX849, and how this drug provides an exciting and long-awaited opportunity to selectively target mutant KRAS in patients.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Mutation; Neoplasms; Protein Prenylation; Proto-Oncogene Proteins p21(ras)
PubMed: 32176377
DOI: 10.1111/joim.13057 -
Nature Chemistry Jun 2019Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras...
Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates the localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here, we report global and selective profiling of prenylated proteins in living cells enabled by the development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease choroideremia.
Topics: Adaptor Proteins, Signal Transducing; Alkynes; Animals; Cell Line; Gene Knockout Techniques; Humans; Mass Spectrometry; Mice, Knockout; Molecular Probes; Protein Prenylation; Proteins; Proteome; Proteomics
PubMed: 30936521
DOI: 10.1038/s41557-019-0237-6 -
Molekuliarnaia Biologiia 2013For their protection from host cell immune defense, intracellular eukaryotic parasites developed a variety of mechanisms, including secretion systems III and IV which... (Review)
Review
For their protection from host cell immune defense, intracellular eukaryotic parasites developed a variety of mechanisms, including secretion systems III and IV which inject bacterial effectors directly into eukaryotic cells. These effectors may be posttranslational modified by host cell machinery and may function inside the host cell. Recently, to the list of possible posttranslational modifications of bacterial proteins the prenylation was added. In this work we describe current state of the knowledge about the prenylation of eukaryotic and prokaryotic proteins and its inhibitors. The bioinformatics analyses suggest possibility of prenylation for a number of Francisella genus proteins.
Topics: Bacteria; Bacterial Proteins; Bacterial Secretion Systems; Computational Biology; Eukaryota; Francisella; Host-Parasite Interactions; Protein Prenylation; Protein Processing, Post-Translational
PubMed: 25509344
DOI: No ID Found -
Nucleus (Austin, Tex.) 2011Lmna yields two major protein products in somatic cells, lamin C and prelamin A. Mature lamin A is produced from prelamin A by four posttranslational processing... (Review)
Review
Lmna yields two major protein products in somatic cells, lamin C and prelamin A. Mature lamin A is produced from prelamin A by four posttranslational processing steps-farnesylation of a carboxyl-terminal cysteine, release of the last three amino acids of the protein, methylation of the farnesylcysteine, and the endoproteolytic release of the carboxyl-terminal 15 amino acids of the protein (including the farnesylcysteine methyl ester). Although the posttranslational processing of prelamin A has been conserved in vertebrate evolution, its physiologic significance remains unclear. Here we review recent studies in which we investigated prelamin A processing with Lmna knock-in mice that produce exclusively prelamin A (Lmna(PLAO)), mature lamin A (Lmna(LAO)) or nonfarnesylated prelamin A (Lmna(nPLAO)). We found that the synthesis of lamin C is dispensable in laboratory mice, that the direct production of mature lamin A (completely bypassing all prelamin A processing) causes no discernable pathology in mice, and that exclusive production of nonfarnesylated prelamin A leads to cardiomyopathy.
Topics: Animals; Lamin Type A; Lamins; Mice; Nuclear Proteins; Progeria; Protein Precursors; Protein Prenylation; Protein Processing, Post-Translational
PubMed: 21647293
DOI: 10.4161/nucl.2.1.13723 -
Current Opinion in Chemical Biology Dec 2012Protein post-translational modifications increase the functional diversity of the proteome by covalently adding chemical moieties onto proteins thereby changing their... (Review)
Review
Protein post-translational modifications increase the functional diversity of the proteome by covalently adding chemical moieties onto proteins thereby changing their activation state, cellular localization, interacting partners, and life cycle. Lipidation is one such modification that enables membrane association of naturally cytosolic proteins. Protein prenyltransferases irreversibly install isoprenoid units of varying length via a thioether linkage onto proteins that exert their cellular activity at membranes. Substrates of prenyltransferases are involved in countless signaling pathways and processes within the cell. Identification of new prenylation substrates, prenylation pathway regulators, and dynamic trafficking of prenylated proteins are all avenues of intense, ongoing research that are challenging, exciting, and have the potential to significantly advance the field in the near future.
Topics: Animals; Bacterial Infections; Bacterial Physiological Phenomena; Dimethylallyltranstransferase; Host-Pathogen Interactions; Humans; Neoplasms; Protein Prenylation; Substrate Specificity
PubMed: 23141597
DOI: 10.1016/j.cbpa.2012.10.015 -
Cell Death & Disease May 2017Statins are a well-established family of drugs that lower cholesterol levels via the competitive inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase...
Statins are a well-established family of drugs that lower cholesterol levels via the competitive inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). In addition, the pleiotropic anti-inflammatory effects of statins on T cells make them attractive as therapeutic drugs in T-cell-driven autoimmune disorders. Since statins do not exclusively target HMGCR and thus might have varying effects on different cell types, we generated a new mouse strain allowing for the tissue-specific deletion of HMGCR. Deletion of HMGCR expression in T cells led to a severe decrease in their numbers with the remaining cells displaying an activated phenotype, with an increased proportion of regulatory T cells (T) in particular. However, deletion of HMGCR specifically in T resulted in severe autoimmunity, suggesting that this enzyme is also essential for the maintenance of T. We were able to prevent the death of HMGCR-deficient lymphocytes by the addition of either the direct metabolite of HMGCR, namely mevalonate, or the downstream metabolite geranylgeranyl pyrophosphate, which is essential for protein prenylation. However, the addition of cholesterol, which is the final product of the mevalonate pathway, did not inhibit cell death, indicating that protein prenylation rather than the cholesterol biosynthesis pathway is indispensible for T-cell survival.
Topics: Animals; Cell Count; Cell Death; Cell Survival; Gene Deletion; Hydroxymethylglutaryl CoA Reductases; Integrases; Lymphocyte Activation; Mevalonic Acid; Mice, Inbred C57BL; Phenotype; Polyisoprenyl Phosphates; Protein Prenylation; T-Lymphocytes; T-Lymphocytes, Regulatory
PubMed: 28542128
DOI: 10.1038/cddis.2017.221 -
Journal of Lipid Research Dec 1992
Review
Topics: Amino Acid Sequence; Animals; Binding Sites; Dimethylallyltranstransferase; Humans; Protein Prenylation; Proteins
PubMed: 1479283
DOI: No ID Found -
Scientific Reports Jul 2016Spermatogenesis in adulthood depends on the successful neonatal establishment of the spermatogonial stem cell (SSC) pool and gradual differentiation during puberty. The...
Spermatogenesis in adulthood depends on the successful neonatal establishment of the spermatogonial stem cell (SSC) pool and gradual differentiation during puberty. The stage-dependent changes in protein prenylation in the seminiferous epithelium might be important during the first round of spermatogenesis before sexual maturation, but the mechanisms are unclear. We have previous found that altered prenylation in Sertoli cells induced spermatogonial apoptosis in the neonatal testis, resulting in adult infertility. Now we further explored the role of protein prenylation in germ cells, using a conditional deletion of geranylgeranyl diphosphate synthase (Ggpps) in embryonic stage and postmeiotic stage respectively. We observed infertility of Ggpps(-/-) Ddx4-Cre mice that displayed a Sertoli-cell-only syndrome phenotype, which resulted from abnormal spermatogonial differentiation and SSC depletion during the prepubertal stage. Analysis of morphological characteristics and cell-specific markers revealed that spermatogonial differentiation was enhanced from as early as the 7(th) postnatal day in the first round of spermatogenesis. Studies of the molecular mechanisms indicated that Ggpps deletion enhanced Rheb farnesylation, which subsequently activated mTORC1 and facilitated spermatogonial differentiation. In conclusion, the prenylation balance in germ cells is crucial for spermatogonial differentiation fate decision during the prepubertal stage, and the disruption of this process results in primary infertility.
Topics: Animals; Animals, Newborn; Cell Differentiation; Chromatography, High Pressure Liquid; Epididymis; Farnesyltranstransferase; Female; Gene Deletion; Gene Expression Regulation; Germ Cells; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Multienzyme Complexes; Phenotype; Protein Prenylation; Ras Homolog Enriched in Brain Protein; Seminiferous Epithelium; Sertoli Cells; Spermatogenesis; Spermatogonia; Stem Cells; Testis
PubMed: 27374985
DOI: 10.1038/srep28917