-
Nature Communications Feb 2023Stimulator of interferon gene (STING)-triggered autophagy is crucial for the host to eliminate invading pathogens and serves as a self-limiting mechanism of...
Stimulator of interferon gene (STING)-triggered autophagy is crucial for the host to eliminate invading pathogens and serves as a self-limiting mechanism of STING-induced interferon (IFN) responses. Thus, the mechanisms that ensure the beneficial effects of STING activation are of particular importance. Herein, we show that myristic acid, a type of long-chain saturated fatty acid (SFA), specifically attenuates cGAS-STING-induced IFN responses in macrophages, while enhancing STING-dependent autophagy. Myristic acid inhibits HSV-1 infection-induced innate antiviral immune responses and promotes HSV-1 replication in mice in vivo. Mechanistically, myristic acid enhances N-myristoylation of ARF1, a master regulator that controls STING membrane trafficking. Consequently, myristic acid facilitates STING activation-triggered autophagy degradation of the STING complex. Thus, our work identifies myristic acid as a metabolic checkpoint that contributes to immune homeostasis by balancing STING-dependent autophagy and IFN responses. This suggests that myristic acid and N-myristoylation are promising targets for the treatment of diseases caused by aberrant STING activation.
Topics: Animals; Mice; Autophagy; Immunity, Innate; Interferons; Membrane Proteins; Myristic Acid; Nucleotidyltransferases; Signal Transduction
PubMed: 36750575
DOI: 10.1038/s41467-023-36332-3 -
Signal Transduction and Targeted Therapy Jan 2023Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Identification of the underlying mechanism of HCC progression and exploration of new...
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed. Here, a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs. A series of functional assays showed that desloratadine, an antiallergic drug, can repress proliferation in HCC cell lines, cell-derived xenograft (CDX), patient-derived organoid (PDO) and patient-derived xenograft (PDX) models. N-myristoyl transferase 1 (NMT1) was identified as a target protein of desloratadine by drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) assays. Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo. Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3 (VILIP3) was a new substrate of NMT1 in protein N-myristoylation modification, and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC. Mechanistically, desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity, disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling. Conclusively, this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Myristic Acid; Protein Processing, Post-Translational
PubMed: 36617552
DOI: 10.1038/s41392-022-01248-9 -
Science (New York, N.Y.) Jul 2019The N-terminal residue influences protein stability through N-degron pathways. We used stability profiling of the human N-terminome to uncover multiple additional...
The N-terminal residue influences protein stability through N-degron pathways. We used stability profiling of the human N-terminome to uncover multiple additional features of N-degron pathways. In addition to uncovering extended specificities of UBR E3 ligases, we characterized two related Cullin-RING E3 ligase complexes, Cul2 and Cul2, that act redundantly to target N-terminal glycine. N-terminal glycine degrons are depleted at native N-termini but strongly enriched at caspase cleavage sites, suggesting roles for the substrate adaptors ZYG11B and ZER1 in protein degradation during apoptosis. Furthermore, ZYG11B and ZER1 were found to participate in the quality control of -myristoylated proteins, in which N-terminal glycine degrons are conditionally exposed after a failure of -myristoylation. Thus, an additional N-degron pathway specific for glycine regulates the stability of metazoan proteomes.
Topics: Animals; Apoptosis; Cell Cycle Proteins; Cullin Proteins; Glycine; Humans; Myristic Acid; Protein Processing, Post-Translational; Protein Stability; Proteolysis; Proteome; Ubiquitin-Protein Ligases
PubMed: 31273098
DOI: 10.1126/science.aaw4912 -
Journal of Food Biochemistry Jan 2022This study evaluated the inhibitory effect of myristic acid (MA) on models of inflammation and nociception. The in vitro anti-inflammatory activities of MA were assessed...
This study evaluated the inhibitory effect of myristic acid (MA) on models of inflammation and nociception. The in vitro anti-inflammatory activities of MA were assessed on LPS-stimulated macrophages, membrane stabilization assay, and inhibition of protein denaturation, whereas the inhibitory activity of MA on in vivo inflammation was assessed on TPA-induced ear edema using acute and chronic assays in mice. The inhibitory effect of MA on nociception was assessed using three in vivo models. MA exerted in vitro anti-inflammatory activity by the increase (58%) in the production of IL-10 in LPS-stimulated macrophages. In the in vivo assay, MA showed good anti-inflammatory effects on the acute (ED = 62 mg/kg) and chronic (ED = 77 mg/kg) TPA-induced ear edema. The antinociceptive activity of MA was related to the participation of the nitrergic system in the formalin-induced paw licking test. PRACTICAL APPLICATIONS: Previous studies with different plant extracts containing MA, as one of their major components, have demonstrated anti-inflammatory and antinociceptive actions. However, the anti-inflammatory and antinociceptive actions of myristic acid have not been previously reported. The results suggest that MA induced anti-inflammatory effects in LPS-stimulated macrophages through the participation of IL-10. The antinociceptive effects of MA are attributed to the participation of the nitrergic system.
Topics: Analgesics; Animals; Inflammation; Mice; Myristic Acid; Nociception; Pain
PubMed: 34811755
DOI: 10.1111/jfbc.14013 -
ACS Omega Jan 2021Microbial glycolipids are one of the most interesting alternatives to chemical-based surfactants as they exhibit improved biodegradability and less toxicity. However,...
Microbial glycolipids are one of the most interesting alternatives to chemical-based surfactants as they exhibit improved biodegradability and less toxicity. However, their potential has been limited because of specificity of the yeast toward fatty acids having a carbon 16 or carbon 18 chain. This study focuses on sophorolipid (SL) production by the yeast using myristic acid, a medium-chain carbon-14 fatty acid that has not been used as a substrate for SL production. The production was optimized for inoculum size and lipophilic substrate concentration. Furthermore, we also studied the effect of medium-chain fatty acid on yeast cell growth and optimized the process for excellent yield. The myristic acid SL (MASL) so synthesized consisted of mono- and diacetylated forms with preferential glycosylation at the methyl end group, as determined by high-resolution mass spectrometry. Individual congeners of the crude mixture were separated using dry column chromatography and then structurally characterized by mass spectrometry. The synthesized MASL was also shown to have promising surface tension, lowering abilities with a low CMC of 14 mg/L. The SL derived from myristic acid exhibited superior antibacterial activity as compared to SL derived from oleic acid. MASL was also found to be more potent against Gram-positive organisms as compared to Gram-negative organisms. This work, therefore, demonstrates successful synthesis of myristic acid-derived SL and its superior antibacterial activity, establishing a promising future for this biosurfactant.
PubMed: 33490786
DOI: 10.1021/acsomega.0c04683 -
Nature Communications Dec 2022N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the...
N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2), recognize N-terminal (Nt) glycine degrons and participate in the Nt-myristoylation quality control through the Gly/N-degron pathway. Here we show that ZER1 and ZYG11B can also recognize small Nt-residues other than glycine. Specifically, ZER1 binds better to Nt-Ser, -Ala, -Thr and -Cys than to -Gly, while ZYG11B prefers Nt-Gly but also has the capacity to recognize Nt-Ser, -Ala and -Cys in vitro. We found that Nt-Ser, -Ala and -Cys undergo Nt-acetylation catalyzed by Nt-acetyltransferase (NAT), thereby shielding them from recognition by ZER1/ZYG11B in cells. Instead, ZER1/ZYG11B readily targets a selection of small Nt-residues lacking Nt-acetylation for degradation in NAT-deficient cells, implicating its role in the Nt-acetylation quality control. Furthermore, we present the crystal structures of ZER1 and ZYG11B bound to various small Nt-residues and uncover the molecular mechanism of non-acetylated substrate recognition by ZER1 and ZYG11B.
Topics: Ubiquitin-Protein Ligases; Protein Processing, Post-Translational; Acetylation; Myristic Acid; Glycine
PubMed: 36496439
DOI: 10.1038/s41467-022-35169-6 -
Annals of Medicine Dec 2023N-myristoyltransferase 1 (NMT1) is an indispensable eukaryotic enzyme that catalyses the transfer of myristoyl groups to the amino acid terminal residues of numerous... (Review)
Review
N-myristoyltransferase 1 (NMT1) is an indispensable eukaryotic enzyme that catalyses the transfer of myristoyl groups to the amino acid terminal residues of numerous proteins. This catalytic process is required for the growth and development of many eukaryotes and viruses. Elevated expression and activity of NMT1 is observed to varying degrees in a variety of tumour types (e.g. colon, lung and breast tumours). Furthermore, an elevated level of NMT1 in tumours is associated with poor survival. Therefore, a relationship exists between NMT1 and tumours. In this review, we discuss the underlying mechanisms by which NMT1 is associated with tumour development from the perspective of oncogene signalling, involvement in cellular metabolism, and endoplasmic reticulum stress. Several NMT inhibitors used in cancer treatment are introduced. The review will provide some directions for future research.Key MessagesElevated expression and activity of NMT1 is observed to varying degrees in a variety of tumour types which creates the possibility of targeting NMT1 in tumours.NMT1-mediated myristoylation plays a pivotal role in cancer cell metabolism and may be particularly relevant to cancer metastasis and drug resistance. These insights can be used to direct potential therapeutic avenues for NMT1 inhibitors.
Topics: Humans; Myristic Acid; Acyltransferases; Lung; Neoplasms
PubMed: 37140999
DOI: 10.1080/07853890.2023.2193425 -
Advances in Neurobiology 2023In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that...
In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that lipids such as phosphoinositides, lysophospholipids, cholesterol, arachidonic acid and myristic acid play critical regulatory roles in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic "hotspots" or by modulating protein functions allosterically. Discrete changes in phosphoinositides concentration are involved in multiple trafficking events including exocytosis and endocytosis. Lipid-modifying enzymes such as the DDHD2 isoform of phospholipase A1 were recently shown to contribute to memory acquisition via dynamic modifications of the brain lipid landscape. Considering the increasing reports on neurodegenerative disorders associated with aberrant intracellular trafficking, an improved understanding of the control of lipid pathways is physiologically and clinically significant and will afford unique insights into mechanisms and therapeutic methods for neurodegenerative diseases. Consequently, this chapter will discuss the different classes of lipids, phospholipase enzymes, the evidence linking them to synaptic neurotransmitter release and how they act to regulate key steps in the multi-step process leading to neuronal communication and memory acquisition.
Topics: Humans; Biological Transport; Brain; Exocytosis; Memory; Phosphatidylinositols; Phospholipases
PubMed: 37615874
DOI: 10.1007/978-3-031-34229-5_14 -
Journal of Personalized Medicine Apr 2021Myristic acid is identified as a metabolite with the highest diagnostic sensitivity and specificity in the metabolome of patients with bacteraemia. Its significant...
Myristic acid is identified as a metabolite with the highest diagnostic sensitivity and specificity in the metabolome of patients with bacteraemia. Its significant decrease has been observed in patients with septic shock not responding to treatment. Another study has reported a close correlation of myristic acid levels with the outcome of severe trauma patients. Myristic acid concentrations were investigated in a cohort of septic patients and patients with Systemic Inflammatory Response Syndrome (SIRS) in 5 consecutive days following diagnosis and compared to healthy controls. The study population groups-Sepsis 34, SIRS 31, and Healthy Control 120 patients were included. Serum samples were analyzed using gas chromatography and mass spectrometry. The myristic acid levels in the Sepsis Group and SIRS Group were found to be significantly higher when compared to healthy controls. The serum concentration of myristic acid in septic patients with bacteraemia was higher than in septic patients without bacteraemia. Most patients with sepsis and SIRS had the highest levels of myristic acid within 24 h after an established diagnosis. Myristic acid should be considered as a new candidate marker of severe inflammation and sepsis. A simplified analysis and sufficient body of validated data are necessary steps towards the introduction of this metabolite into routine clinical practice.
PubMed: 33923419
DOI: 10.3390/jpm11040306