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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 -
Plant Physiology Jun 2024Rho of Plant (ROP) GTPases function as molecular switches that control signaling processes essential for growth, development, and defense. However, their role in...
Rho of Plant (ROP) GTPases function as molecular switches that control signaling processes essential for growth, development, and defense. However, their role in specialized metabolism is poorly understood. Previously, we demonstrated that inhibition of protein geranylgeranyl transferase (PGGT-I) negatively impacts the biosynthesis of monoterpene indole alkaloids (MIA) in Madagascar periwinkle (Catharanthus roseus), indicating the involvement of prenylated proteins in signaling. Here, we show through biochemical, molecular, and in planta approaches that specific geranylgeranylated ROPs modulate C. roseus MIA biosynthesis. Among the six C. roseus ROP GTPases (CrROPs), only CrROP3 and CrROP5, having a C-terminal CSIL motif, were specifically prenylated by PGGT-I. Additionally, their transcripts showed higher expression in most parts than other CrROPs. Protein-protein interaction studies revealed that CrROP3 and CrROP5, but not ΔCrROP3, ΔCrROP5, and CrROP2 lacking the CSIL motif, interacted with CrPGGT-I. Further, CrROP3 and CrROP5 exhibited nuclear localization, whereas CrROP2 was localized to the plasma membrane. In planta functional studies revealed that silencing of CrROP3 and CrROP5 negatively affected MIA biosynthesis, while their overexpression upregulated MIA formation. In contrast, silencing and overexpression of CrROP2 had no effect on MIA biosynthesis. Moreover, overexpression of ΔCrROP3 and ΔCrROP5 mutants devoid of sequence coding for the CSIL motif failed to enhance MIA biosynthesis. These results implicate that CrROP3 and CrROP5 have a positive regulatory role on MIA biosynthesis and thus shed light on how geranylgeranylated ROP GTPases mediate the modulation of specialized metabolism in C. roseus.
Topics: Catharanthus; Plant Proteins; Gene Expression Regulation, Plant; Protein Prenylation; Amino Acid Motifs; Alkaloids
PubMed: 38466200
DOI: 10.1093/plphys/kiae142 -
Physiological Reports Mar 2024Fast-twitch muscles are less susceptible to disuse atrophy, activate the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, and increase protein...
Fast-twitch muscles are less susceptible to disuse atrophy, activate the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, and increase protein synthesis under prolonged muscle disuse conditions. However, the mechanism underlying prolonged muscle disuse-induced mTORC1 signaling activation remains unclear. The mevalonate pathway activates the mTORC1 signaling pathway via the prenylation and activation of Ras homolog enriched in brain (Rheb). Therefore, we investigated the effects of hindlimb unloading (HU) for 14 days on the mevalonate and mTORC1 signaling pathways in the plantaris muscle, a fast-twitch muscle, in adult male rats. Rats were divided into HU and control groups. The plantaris muscles of both groups were harvested after the treatment period, and the expression and phosphorylation levels of metabolic and intracellular signaling proteins were analyzed using Western blotting. We found that HU increased the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme of the mevalonate pathway, and activated the mTORC1 signaling pathway without activating AKT, an upstream activator of mTORC1. Furthermore, HU increased prenylated Rheb. Collectively, these findings suggest that the activated mevalonate pathway may be involved in the activation of the Rheb/mTORC1 signaling pathway without AKT activation in fast-twitch muscles under prolonged disuse conditions.
Topics: Rats; Male; Animals; Mechanistic Target of Rapamycin Complex 1; Mevalonic Acid; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Hindlimb Suspension; Signal Transduction; Muscle, Skeletal; Muscular Atrophy
PubMed: 38453353
DOI: 10.14814/phy2.15969 -
Yeast (Chichester, England) May 2024Lipid binding domains and protein lipidations are essential features to recruit proteins to intracellular membranes, enabling them to function at specific sites within... (Review)
Review
Lipid binding domains and protein lipidations are essential features to recruit proteins to intracellular membranes, enabling them to function at specific sites within the cell. Membrane association can also be exploited to answer fundamental and applied research questions, from obtaining insights into the understanding of lipid metabolism to employing them for metabolic engineering to redirect fluxes. This review presents a broad catalog of membrane binding strategies focusing on the plasma membrane of Saccharomyces cerevisiae. Both lipid binding domains (pleckstrin homology, discoidin-type C2, kinase associated-1, basic-rich and bacterial phosphoinositide-binding domains) and co- and post-translational lipidations (prenylation, myristoylation and palmitoylation) are introduced as tools to target the plasma membrane. To provide a toolset of membrane targeting modules, respective candidates that facilitate plasma membrane targeting are showcased including their in vitro and in vivo properties. The relevance and versatility of plasma membrane targeting modules are further highlighted by presenting a selected set of use cases.
Topics: Saccharomyces cerevisiae; Cell Membrane; Saccharomyces cerevisiae Proteins; Membrane Proteins; Protein Transport; Lipid Metabolism
PubMed: 38444057
DOI: 10.1002/yea.3933 -
MBio Apr 2024is a widespread intracellular protozoan pathogen infecting virtually all warm-blooded animals. This parasite acquires host-derived resources to support its replication...
is a widespread intracellular protozoan pathogen infecting virtually all warm-blooded animals. This parasite acquires host-derived resources to support its replication inside a membrane-bound parasitophorous vacuole within infected host cells. Previous research has discovered that actively endocytoses host proteins and transports them to a lysosome-equivalent structure for digestion. However, few molecular determinants required for trafficking of host-derived material within the parasite were known. A recent study (Q.-Q. Wang, M. Sun, T. Tang, D.-H. Lai, et al., mBio 14:e01309-23, 2023, https://doi.org/10.1128/mbio.01309-23) identified a critical role for membrane anchoring of proteins via prenylation in the trafficking of endocytosed host proteins by , including an essential ortholog of Rab1B. The authors also found that TgRab1 is crucial for protein trafficking of the rhoptry secretory organelles, indicating a dual role in endocytic and exocytic protein trafficking. This study sets the stage for further dissecting endomembrane trafficking in , along with potentially exploiting protein prenylation as a target for therapeutic development.
Topics: Animals; Toxoplasma; Protein Prenylation; Proteins; Organelles; Protein Transport
PubMed: 38407123
DOI: 10.1128/mbio.00283-24 -
Bioorganic Chemistry Apr 2024Human serum albumin (HSA) is a serum protein that carries flavonoids in blood circulation. In this report, the binding selectivity and strength of interactions to...
Human serum albumin (HSA) is a serum protein that carries flavonoids in blood circulation. In this report, the binding selectivity and strength of interactions to HSA-binding sites (sites I or II) by flavonoids were evaluated using competition experiments and the specific fluorescent dyes, dansylamide and BD140. Most tested flavonoids bound site I preferentially, with the binding strength dependent on the mother structure in the order flavonol > flavone > flavanone > flavan 3-ols. Glycosylation or glucuronidation reduced the binding of quercetin to site I of HSA, whereas sulfation increased binding. Quercetin 7-sulfate showed the strongest binding and molecular docking simulations supported this observation. Prenylation at any position or glucuronidation and sulfation at the C-4' or C-7 position of quercetin facilitated stronger binding to site II. The binding affinity of flavonoids toward site I correlated with the partition coefficient value (logP), whereas no corresponding correlation was observed for site II.
Topics: Humans; Serum Albumin, Human; Quercetin; Polyphenols; Fluorescent Dyes; Molecular Docking Simulation; Flavonoids; Binding Sites; Protein Binding; Spectrometry, Fluorescence
PubMed: 38364549
DOI: 10.1016/j.bioorg.2024.107184 -
Phytotherapy Research : PTR Apr 2024The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens...
The anti-inflammatory activity of flavonoids and alkaloids from Sophora flavescens alleviates psoriasiform lesions: Prenylation and methoxylation beneficially enhance bioactivity and skin targeting.
The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.
Topics: Mice; Animals; Flavonoids; Sophora flavescens; Sophora; Flavanones; Prenylation; Anti-Inflammatory Agents; Alkaloids; Cytokines; Chemokines
PubMed: 38358770
DOI: 10.1002/ptr.8140 -
International Journal of Dermatology Jun 2024Cutaneous fungal infections affect millions around the world. However, severe, multi-resistant fungal infections are increasingly being reported over the past years. As... (Review)
Review
Cutaneous fungal infections affect millions around the world. However, severe, multi-resistant fungal infections are increasingly being reported over the past years. As a result of the high rate of resistance which urged for drug repurposing, statins were studied and found to have multiple pleiotropic effects, especially when combined with other already-existing drugs. An example of this is the synergism found between several typical antifungals and statins, such as antifungals Imidazole and Triazole with a wide range of statins shown in this review. The main mechanisms in which they exert an antifungal effect are ergosterol inhibition, protein prenylation, mitochondrial disruption, and morphogenesis/mating inhibition. This article discusses multiple in vitro studies that have proven the antifungal effect of systemic statins against many fungal species, whether used alone or in combination with other typical antifungals. However, as a result of the high rate of drug-drug interactions and the well-known side effects of systemic statins, topical statins have become of increasing interest. Furthermore, patients with dyslipidemia treated with systemic statins who have a new topical fungal infection could benefit from the antifungal effect of their statin. However, it is still not indicated to initiate systemic statins in patients with topical mycotic infections if they do not have another indication for statin use, which raises the interest in using topical statins for fungal infections. This article also tackles the different formulations that have been studied to enhance topical statins' efficacy, as well as the effect of different topical statins on distinct dermatologic fungal diseases.
Topics: Humans; Antifungal Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dermatomycoses; Administration, Cutaneous; Drug Repositioning; Drug Interactions
PubMed: 38344878
DOI: 10.1111/ijd.17068 -
Journal of Lipid Research Mar 2024LDL-C lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a...
LDL-C lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin-induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin-mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small-molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin-mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post-transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.
Topics: Mice; Animals; Proprotein Convertase 9; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Antibodies, Monoclonal; Cholesterol
PubMed: 38309417
DOI: 10.1016/j.jlr.2024.100515 -
Biochimie Jul 2024Isoprenyl cysteine carboxyl methyltransferase (ICMT) catalyzes the last step of the prenylation pathway. Previously, we found that high ICMT levels enhance tumorigenesis...
Isoprenyl cysteine carboxyl methyltransferase (ICMT) catalyzes the last step of the prenylation pathway. Previously, we found that high ICMT levels enhance tumorigenesis in vivo and that its expression is repressed by the p53 tumor suppressor. Based on evidence suggesting that some ICMT substrates affect invasive traits, we wondered if this enzyme may promote metastasis. In this work, we found that ICMT overexpression enhanced lung metastasis in vivo. Accordingly, ICMT overexpression also promoted cellular functions associated with aggressive phenotypes such as migration and invasion in vitro. Considering that some ICMT substrates are involved in the regulation of actin cytoskeleton, we hypothesized that actin-rich structures, associated with invasion and metastasis, may be affected. Our findings revealed that ICMT enhanced the formation of invadopodia. Additionally, by analyzing cancer patient databases, we found that ICMT is overexpressed in several tumor types. Furthermore, the concurrent expression of ICMT and CTTN, which encodes a crucial component of invadopodia, showed a significant correlation with clinical outcome. In summary, our work identifies ICMT overexpression as a relevant alteration in human cancer that promotes the development of metastatic tumors.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Movement; Cortactin; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Podosomes; Protein Methyltransferases
PubMed: 38301884
DOI: 10.1016/j.biochi.2024.01.015