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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 -
Microbiome Feb 2022Gut microbiota contributes to colorectal cancer (CRC) pathogenesis through microbes and their metabolites. The importance of microbiota-associated metabolites in...
BACKGROUND
Gut microbiota contributes to colorectal cancer (CRC) pathogenesis through microbes and their metabolites. The importance of microbiota-associated metabolites in colorectal carcinogenesis highlights the need to investigate the gut metabolome along the adenoma-carcinoma sequence to determine their mechanistic implications in the pathogenesis of CRC. To date, how and which microbes and metabolites interactively promote early events of CRC development are still largely unclear. We aim to determine gut microbiota-associated metabolites and their linkage to colorectal carcinogenesis.
RESULTS
We performed metabolomics and metagenomics profiling on fecal samples from 386 subjects including 118 CRC patients, 140 colorectal adenomas (CRA) patients and 128 healthy subjects as normal controls (NC). We identified differences in the gut metabolite profiles among NC, CRA and CRC groups by partial least squares-discriminant and principal component analyses. Among the altered metabolites, norvaline and myristic acid showed increasing trends from NC, through CRA, to CRC. CRC-associated metabolites were enriched in branched-chain amino acids, aromatic amino acids and aminoacyl-tRNA biosynthesis pathways. Moreover, metabolites marker signature (twenty metabolites) classified CRC from NC subjects with an area under the curve (AUC) of 0.80, and CRC from CRA with an AUC of 0.79. Integrative analyses of metabolomics and metagenomics profiles demonstrated that the relationships among CRC-associated metabolites and bacteria were altered across CRC stages; certain associations exhibited increasing or decreasing strengths while some were reversed from negative to positive or vice versa. Combinations of gut bacteria with the metabolite markers improved their diagnostic performances; CRC vs NC, AUC: 0.94; CRC vs CRA, AUC 0.92; and CRA vs NC, AUC: 0.86, indicating a potential for early diagnosis of colorectal neoplasia.
CONCLUSIONS
This study underscores potential early-driver metabolites in stages of colorectal tumorigenesis. The Integrated metabolite and microbiome analysis demonstrates that gut metabolites and their association with gut microbiota are perturbed along colorectal carcinogenesis. Fecal metabolites can be utilized, in addition to bacteria, for non-invasive diagnosis of colorectal neoplasia. Video Abstract.
Topics: Adenoma; Carcinogenesis; Colorectal Neoplasms; Feces; Gastrointestinal Microbiome; Humans; Microbiota
PubMed: 35189961
DOI: 10.1186/s40168-021-01208-5 -
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 -
Frontiers in Nutrition 2022Evidence regarding associations of circulating saturated fatty acids (SFAs) with chronic diseases is mixed. The objective of this study was to determine the associations...
BACKGROUND AND AIMS
Evidence regarding associations of circulating saturated fatty acids (SFAs) with chronic diseases is mixed. The objective of this study was to determine the associations between total or individual SFA biomarkers and the risk of cardiometabolic diseases.
METHODS
Four electronic databases were searched from inception to March 2022. Three investigators independently assessed for inclusion and extracted data. Random-effects or fixed-effects models was used to estimate the pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) for the association of total or individual SFA biomarkers, including even-chain SFAs (e.g., 14:0, myristic acid; 16:0, palmitic acid; 18:0, stearic acid), odd-chain SFAs (e.g., 15:0, pentadecanoic acid; 17:0, margaric acid) and very-long-chain SFAs (VLCSFAs; e.g., 20:0, arachidic acid; 22:0, behenic acid; 24:0, lignoceric acid), with risk of incident type 2 diabetes (T2D), cardiovascular disease [CVD; coronary heart disease (CHD) inclusive of stroke], CHD and stroke.
RESULTS
A total of 49 prospective studies reported in 45 articles were included. Higher concentration of circulating total SFAs was associated with an increasing risk of cardiometabolic diseases, the risk increased significantly by 50% for CVD (95%CI:1.31-1.71), 63% for CHD (95%CI:1.38-1.94), 38% for stroke (95%CI:1.05-1.82), respectively. Similarly, levels of even-chain SFAs were positively associated with higher risk of chronic diseases, with RRs ranging from 1.15 to 1.43. In contrast, the risk of cardiometabolic diseases was reduced with increasing odd-chain SFA levels, with RRs ranging from 0.62 to 0.91. A higher level of VLCSFAs corresponded to 19% reduction in CVD. Further dose-response analysis indicated that each 50% increment in percentage of total SFAs in circulating was associated with an 8% higher risk of T2D (RR: 1.08, 95%CI: 1.02-1.14) and trends toward higher risk of CVD (RR: 1.15, 95%CI: 0.98-1.34). Inverse linear relationships were observed between 17:0 biomarker and T2D or CVD risk.
CONCLUSION
Our findings support the current recommendations of reducing intake of saturated fat as part of healthy dietary patterns. Further studies are needed to confirm our findings on these SFAs in relation to cardiometabolic outcomes and to elucidate underlying mechanisms.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022329182], identifier [CRD42022329182].
PubMed: 36046138
DOI: 10.3389/fnut.2022.963471 -
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 -
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 -
Frontiers in Nutrition 2022Previous studies have shown that myristic acid (MA), a saturated fatty acid, could promote the proliferation and differentiation of neural stem cells . However, the...
Previous studies have shown that myristic acid (MA), a saturated fatty acid, could promote the proliferation and differentiation of neural stem cells . However, the effect of MA on hippocampal neurons aging has not been reported . Here we employed 22-month-old naturally aged C57BL/6 mice to evaluate the effect and mechanism of MA on hippocampal aging. First, we examined a decreased exploration and spatial memory ability in aging mice using the open field test and Morris water maze. Consistently, aging mice showed degenerative hippocampal histomorphology by H&E and Nissl staining. In terms of mechanism, imbalance of GABRB2 and GABRA2 expression in aging mice might be involved in hippocampus aging by mRNA high throughput sequencing (mRNA-seq) and immunohistochemistry (IHC) validation. Then, we revealed that MA alleviated the damage of exploration and spatial memory ability and ameliorated degeneration and aging of hippocampal neurons. Meanwhile, MA downregulated GABRB2 and upregulated GABRA2 expression, indicating MA might alleviate hippocampal aging correlated with GABAergic signaling. In conclusion, our findings revealed MA alleviated hippocampal aging correlated with GABAergic signaling, which might provide insight into the treatment of aging-associated diseases.
PubMed: 36159502
DOI: 10.3389/fnut.2022.907526