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Trends in Molecular Medicine May 2022Choroideremia (CHM) is a monogenic X-linked chorioretinal dystrophy affecting the photoreceptors, retinal pigment epithelium (RPE), and choroid; it is caused by... (Review)
Review
Choroideremia (CHM) is a monogenic X-linked chorioretinal dystrophy affecting the photoreceptors, retinal pigment epithelium (RPE), and choroid; it is caused by mutations involving the CHM gene. CHM is characterized by night blindness in early childhood, progressing to peripheral visual field loss and eventually to complete blindness from middle age. CHM encodes the ubiquitously expressed Rab escort protein 1 (REP1), which is responsible for prenylation of Rab proteins and is essential for intracellular trafficking of vesicles. In this review we explore the role of REP1 in the retina and its newly discovered systemic manifestations, and discuss the therapeutic strategies for tackling this disease, including the outcomes from recent clinical trials.
Topics: Adaptor Proteins, Signal Transducing; Child, Preschool; Choroid; Choroideremia; Humans; Middle Aged; Mutation; Retina; Retinal Pigment Epithelium
PubMed: 35341685
DOI: 10.1016/j.molmed.2022.02.011 -
Molecular Reproduction and Development 2023Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes... (Review)
Review
Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes and is an essential pathway for cholesterol production and protein prenylation. Male reproductive aging is accompanied by dramatic changes in the metabolic microenvironment of the testis. Since the mevalonate pathway has an important role in spermatogenesis, we attempted to explore the association between male reproductive aging and the mevalonate pathway to explain the mechanism of male reproductive aging. Alterations in the mevalonate pathway may affect male reproductive aging by decreasing cholesterol synthesis and altering testis protein prenylation. Decreased cholesterol levels affect cholesterol modification, testosterone production, and remodeling of germ cell membranes. Aging-related metabolic disorders also affect the metabolic coupling between somatic cells and spermatogenic cells, leading to male fertility decline. Therefore, we hypothesized that alterations in the mevalonate pathway represent one of the metabolic causes of reproductive aging.
Topics: Male; Humans; Mevalonic Acid; Cholesterol; Reproduction; Testis
PubMed: 37733694
DOI: 10.1002/mrd.23705 -
Molecules (Basel, Switzerland) Oct 2019Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental... (Review)
Review
Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental processes as well as stress responses in plants as the addition of hydrophobic prenyl chains (mostly farnesyl or geranyl) allow otherwise hydrophilic proteins to operate as peripheral lipid membrane proteins. This review focuses on selected aspects connecting protein prenylation with plant responses to both abiotic and biotic stresses. It summarizes how changes in protein prenylation impact plant growth, deals with several families of proteins involved in stress response and highlights prominent regulatory importance of prenylated small GTPases and chaperons. Potential possibilities of these proteins to be applicable for biotechnologies are discussed.
Topics: Biotechnology; Plant Proteins; Plants; Protein Prenylation; Stress, Physiological; Substrate Specificity
PubMed: 31671559
DOI: 10.3390/molecules24213906 -
Small GTPases Jan 2020Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases... (Review)
Review
Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N- and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them. Similar to Rac and Cdc42, they interact with PAK serine/threonine kinases, and in the case of PAK4, this interaction leads to RhoU protein stabilization. In cells, RhoU and RhoV alter cell shape and cell adhesion, which probably underlies some of the phenotypes reported for these proteins , for example in heart development and epithelial morphogenesis. However, the molecular basis for these functions of RhoU and RhoV remains to be characterized.
Topics: Animals; Humans; Protein Transport; Signal Transduction; rho GTP-Binding Proteins
PubMed: 29189096
DOI: 10.1080/21541248.2017.1362495 -
The Journal of Biological Chemistry Apr 2023Liver kinase B1 (LKB1) is a serine-threonine kinase that participates in multiple cellular and biological processes, including energy metabolism, cell polarity, cell... (Review)
Review
Liver kinase B1 (LKB1) is a serine-threonine kinase that participates in multiple cellular and biological processes, including energy metabolism, cell polarity, cell proliferation, cell migration, and many others. LKB1 is initially identified as a germline-mutated causative gene in Peutz-Jeghers syndrome and is commonly regarded as a tumor suppressor due to frequent inactivation in a variety of cancers. LKB1 directly binds and activates its downstream kinases including the AMP-activated protein kinase (AMPK) and AMPK-related kinases by phosphorylation, which has been intensively investigated for the past decades. An increasing number of studies have uncovered the posttranslational modifications (PTMs) of LKB1 and consequent changes in its localization, activity, and interaction with substrates. The alteration in LKB1 function as a consequence of genetic mutations and aberrant upstream signaling regulation leads to tumor development and progression. Here, we review current knowledge about the mechanism of LKB1 in cancer and the contributions of PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, prenylation, and others, to the regulation of LKB1 function, offering new insights into the therapeutic strategies in cancer.
Topics: Humans; AMP-Activated Protein Kinases; Liver; Peutz-Jeghers Syndrome; Phosphorylation; Protein Serine-Threonine Kinases; Neoplasms; Protein Processing, Post-Translational
PubMed: 36870679
DOI: 10.1016/j.jbc.2023.104570 -
Signal Transduction and Targeted Therapy Mar 2024Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes. Among these,... (Review)
Review
Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes. Among these, protein lipidations which refer to lipid attachment to proteins are prominent, which primarily encompassing five types including S-palmitoylation, N-myristoylation, S-prenylation, glycosylphosphatidylinositol (GPI) anchor and cholesterylation. Lipid attachment to proteins plays an essential role in the regulation of protein trafficking, localisation, stability, conformation, interactions and signal transduction by enhancing hydrophobicity. Accumulating evidence from genetic, structural, and biomedical studies has consistently shown that protein lipidation is pivotal in the regulation of broad physiological functions and is inextricably linked to a variety of diseases. Decades of dedicated research have driven the development of a wide range of drugs targeting protein lipidation, and several agents have been developed and tested in preclinical and clinical studies, some of which, such as asciminib and lonafarnib are FDA-approved for therapeutic use, indicating that targeting protein lipidations represents a promising therapeutic strategy. Here, we comprehensively review the known regulatory enzymes and catalytic mechanisms of various protein lipidation types, outline the impact of protein lipidations on physiology and disease, and highlight potential therapeutic targets and clinical research progress, aiming to provide a comprehensive reference for future protein lipidation research.
Topics: Lipid Metabolism; Proteins; Protein Processing, Post-Translational; Signal Transduction; Lipids
PubMed: 38485938
DOI: 10.1038/s41392-024-01759-7 -
Trends in Cancer Jun 2021The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered... (Review)
Review
The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered supportive roles for the mevalonate pathway in numerous cellular processes that support oncogenesis, most recently macropinocytosis. Central to the diverse mechanisms of statin sensitivity is an acquired dependence on one mevalonate pathway output, protein geranylgeranylation. New chemical prenylation probes and the discovery of a novel geranylgeranyl transferase hold promise to deepen our understanding of statin mechanisms of action. Further, insights into statin selection and the counterproductive role of dietary geranylgeraniol highlight how we should assess statins in the clinic. Lastly, rational combination strategies preview how statins will enter the oncology toolbox.
Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Diterpenes; Farnesyltranstransferase; Feeding Behavior; Food-Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metabolic Networks and Pathways; Mevalonic Acid; Mice; Neoplasms; Pinocytosis; Polyisoprenyl Phosphates; Prenylation
PubMed: 33358111
DOI: 10.1016/j.trecan.2020.11.008 -
Journal of Natural Medicines Jun 2020Aromatic prenyltransferases (PTases), including ABBA-type and dimethylallyl tryptophan synthase (DMATS)-type enzymes from bacteria and fungi, play important role for... (Review)
Review
Aromatic prenyltransferases (PTases), including ABBA-type and dimethylallyl tryptophan synthase (DMATS)-type enzymes from bacteria and fungi, play important role for diversification of the natural products and improvement of the biological activities. For a decade, the characterization of enzymes and enzymatic synthesis of prenylated compounds by using ABBA-type and DMATS-type PTases have been demonstrated. Here, I introduce several examples of the studies on chemoenzymatic synthesis of unnatural prenylated compounds and the enzyme engineering of ABBA-type and DMATS-type PTases.
Topics: Alkyl and Aryl Transferases; Bacteria; Biological Products; Dimethylallyltranstransferase; Fungi; Prenylation; Protein Engineering
PubMed: 32180104
DOI: 10.1007/s11418-020-01393-x -
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 -
International Journal of Molecular... May 2022Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras... (Review)
Review
Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras superfamily. This covalent attachment of either a farnesyl (15 carbon) or a geranylgeranyl (20 carbon) isoprenoid group is catalyzed by four prenyltransferases, namely farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), Rab geranylgeranyltransferase (GGTase-II), and recently discovered geranylgeranyltransferase type III (GGTase-III). Blocking small GTPase activity, namely inhibiting prenyltransferases, has been proposed as a potential disease treatment method. Inhibitors of prenyltransferase have resulted in substantial therapeutic benefits in various diseases, such as cancer, neurological disorders, and viral and parasitic infections. In this review, we overview the structure of FTase, GGTase-I, GGTase-II, and GGTase-III and summarize the current status of research on their inhibitors.
Topics: Carbon; Dimethylallyltranstransferase; Farnesyltranstransferase; Protein Prenylation; Terpenes
PubMed: 35628237
DOI: 10.3390/ijms23105424