bims-polyam 2023-02-05 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–02–05
twelve papers selected by
Sebastian J. Hofer, University of Graz

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a novel mouse model of Snyder-Robinson Syndrome.
Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.
Probiotic induced synthesis of microbiota polyamine as a nutraceutical for metabolic syndrome and obesity-related type 2 diabetes.
Administration of spermidine attenuates concanavalin A-induced liver injury.
P5-ATPases: Structure, substrate specificities, and transport mechanisms.
Inhibition of chikungunya virus replication by N-ω-Chloroacetyl-L-Ornithine in C6/36, Vero cells and human fibroblast BJ.
Extensive diversity in RNA termination and regulation revealed by transcriptome mapping for the Lyme pathogen B. burgdorferi.
Identification of a polyamine-related signature and six novel prognostic biomarkers in oral squamous cell carcinoma.
Post-fast refeeding enhances intestinal stem cell-mediated regeneration and tumourigenesis through mTORC1-dependent polyamine synthesis.
Polyamines and nitric oxide crosstalk in plant development and abiotic stress tolerance.
Circular RNA circ_0003028 regulates cell development through modulating miR-498/ornithine decarboxylase 1 axis in hepatocellular carcinoma.
Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS.

bioRxiv. 2023 Jan 17. pii: 2023.01.15.524155. [Epub ahead of print]

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a novel mouse model of Snyder-Robinson Syndrome.

Oluwaseun Akinyele, Anushe Munir, Marie Johnson, Megan E Perez, Yuan Gao, Jackson R Foley, Yijen Wu, Tracy Murray-Stewart, Robert Casero, Hulya Bayir, Dwi U Kemaladewi.

Polyamines (putrescine, spermidine, and spermine) are essential for cellular growth and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to the accumulation of spermidine and an X-linked recessive disorder known as Snyder-Robinson syndrome (SRS). There are no treatments available for this rare disease that manifests as mental retardation, thin habitus, and low muscle tone. The development of therapeutic interventions for SRS will require a suitable disease-specific animal model that recapitulates many of the abnormalities observed in these patients. Here, we characterize the molecular, behavioral, and neuroanatomical features of a mouse model with a missense mutation in Sms that results in a glycine-to-serine substitution at position 56 (G56S) of the SMS protein. Mice harboring this mutation exhibited a complete loss of SMS protein and elevated spermidine/spermine ratios in skeletal muscles and the brain. In addition, the G56S mice demonstrated increased anxiety, impaired learning, and decreased explorative behavior in fear conditioning, Morris water maze, and open field tests, respectively. Furthermore, the mice undergo significant reductions in body weight over time, as well as abnormalities in brain structure and bone density. Transcriptomic analysis of the cerebral cortex revealed downregulation of genes associated with mitochondrial oxidative phosphorylation and synthesis of ribosomal proteins. Our findings also revealed impaired mitochondrial bioenergetics in fibroblasts isolated from the G56S mice, which provides a link between these processes and the pathogenesis of SRS. Collectively, our findings establish the first in-depth characterization of SRS-associated mechanisms in a preclinical animal model and identify cellular processes that can be targeted for future therapeutic development.

DOI: https://doi.org/10.1101/2023.01.15.524155
Blood. 2023 Feb 03. pii: blood.2022017584. [Epub ahead of print]

Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.

Pedro Gonzalez-Menendez, Ira Phadke, Meagan E Olive, Axel Joly, Julien Papoin, Hongxia Yan, Jérémy Galtier, Jessica Platon, Sun Woo Sophie Kang, Kathy L McGraw, Marie Daumur, Marie Pouzolles, Taisuke Kondo, Stéphanie Boireau, Franciane Paul, David J Young, Sylvain Lamure, Raghavendra G Mirmira, Anu Narla, Guillaume Cartron, Cynthia E Dunbar, Myriam Boyer-Clavel, Natalie Porat-Shliom, Valerie Dardalhon, Valerie S Zimmermann, Marc Sitbon, Thomas Dever, Narla Mohandas, Lydie M Da Costa, Namrata D Udeshi, Lionel Blanc, Sandrina Kinet, Naomi Taylor.

Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors--by inhibition of deoxyhypusine synthase--abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation.

DOI: https://doi.org/10.1182/blood.2022017584
Front Endocrinol (Lausanne). 2022 ;13 1094258

Probiotic induced synthesis of microbiota polyamine as a nutraceutical for metabolic syndrome and obesity-related type 2 diabetes.

Tina I Bui, Emily A Britt, Gowrishankar Muthukrishnan, Steven R Gill.

  The gut microbiota regulates multiple facets of host metabolism and immunity through the production of signaling metabolites, such as polyamines which are small organic compounds that are essential to host cell growth and lymphocyte activation. Polyamines are most abundant in the intestinal lumen, where their synthesis by the gut microbiota is influenced by microbiome composition and host diet. Disruption of the host gut microbiome in metabolic syndrome and obesity-related type 2 diabetes (obesity/T2D) results in potential dysregulation of polyamine synthesis. A growing body of evidence suggests that restoration of the dysbiotic gut microbiota and polyamine synthesis is effective in ameliorating metabolic syndrome and strengthening the impaired immune responses of obesity/T2D. In this review, we discuss existing studies on gut microbiome determinants of polyamine synthesis, polyamine production in obesity/T2D, and evidence that demonstrates the potential of polyamines as a nutraceutical in obesity/T2D hosts.

Keywords:  metabolic syndrome; nutraceutical; obesity; polyamine; type 2 diabetes

DOI:  https://doi.org/10.3389/fendo.2022.1094258
Biochem Biophys Res Commun. 2023 Jan 23. pii: S0006-291X(23)00103-1. [Epub ahead of print]648 44-49

Administration of spermidine attenuates concanavalin A-induced liver injury.

Tatusya Ando, Daisuke Ito, Kazuya Shiogama, Yasuhiro Sakai, Masato Abe, Takayasu Ideta, Ayumu Kanbe, Masahito Shimizu, Hiroyasu Ito.

  A previous study revealed that treatment with the anticoagulant heparin attenuated concanavalin A (ConA)-induced liver injury. The administration of spermidine (SPD) increased urokinase-type plasminogen activator (uPA) levels in the serum. uPA is clinically used for the treatment of some thrombotic diseases such as cerebral infarction. Therefore, SPD may attenuate ConA-induced liver injury that is exacerbated by blood coagulation. The present study investigated the effect of SPD on liver injury in mice with autoimmune hepatopathy induced by ConA. A model of liver injury was created by intravenous injection of ConA into mice. SPD was administered in free drinking water and was biochemically and pathologically examined over time. The administration of SPD to ConA-treated mice significantly reduced liver injury. However, SPD treatment upregulated the mRNA expression of TNF-α and IFN-ϒ in the livers of ConA-treated mice. In contrast, the mRNA expression of tissue factor in the livers of SPD-treated mice was decreased after ConA injection. The frequency of lymphocytes and lymphocyte activation were not affected by SPD administration in ConA-treated mice. SPD treatment increased uPA levels in the serum and decreased the level of D-dimer in ConA-treated mice. Moreover, SPD decreased fibrin in the livers of ConA-treated mice. These results indicated that SPD treatment increased anticoagulant ability by increasing of uPA and attenuated ConA-induced liver injury.

Keywords:  Autoimmune hepatitis; Coagulation; Spermidine (SPD)

DOI:  https://doi.org/10.1016/j.bbrc.2023.01.072
Curr Opin Struct Biol. 2023 Jan 30. pii: S0959-440X(23)00005-2. [Epub ahead of print]79 102531

P5-ATPases: Structure, substrate specificities, and transport mechanisms.

Sue Im Sim, Eunyong Park.

  P5A- and P5B- ATPases, or collectively P5-ATPases, are eukaryotic-specific ATP-dependent transporters that are important for the function of the endoplasmic reticulum (ER) and endo-/lysosomes. However, their substrate specificities had remained enigmatic for many years. Recent cryo-electron microscopy (cryo-EM) and biochemical studies of P5-ATPases have revealed their substrate specificities and transport mechanisms, which were found to be markedly different from other members of the P-type ATPase superfamily. The P5A-ATPase extracts mistargeted or mis-inserted transmembrane helices from the ER membrane for protein quality control, while the P5B-ATPases mediate export of polyamines from late endo-/lysosomes into the cytosol. In this review, we discuss the mechanisms of their substrate recognition and transport based on the cryo-EM structures of the yeast and human P5-ATPases. We highlight how structural diversification of the transmembrane domain has enabled the P5-ATPase subfamily to adapt for transport of atypical substrates.

Keywords:  Endoplasmic reticulum; Kufor Rakeb syndrome; Lysosomes; P-type ATPases; P5-ATPases; Parkinson's disease; Polyamine; Protein quality control; Tail-anchored membrane proteins

DOI:  https://doi.org/10.1016/j.sbi.2023.102531
Antivir Ther. 2023 Feb;28(1): 13596535231155263

Inhibition of chikungunya virus replication by N-ω-Chloroacetyl-L-Ornithine in C6/36, Vero cells and human fibroblast BJ.

Lucero Rojas-Luna, Araceli Posadas-Modragón, Amanda M Avila-Trejo, Verónica Alcántara-Farfán, Lorena I Rodríguez-Páez, José Angel Santiago-Cruz, Marvin O Pastor-Alonso, J Leopoldo Aguilar-Faisal.

   BACKGROUND: Polyamines are involved in several cellular processes and inhibiting their synthesis affects chikungunya virus (CHIKV) replication and translation, and, therefore, reduces the quantity of infectious viral particles produced. In this study, we evaluated the inhibition of CHIKV replication by N-ω-chloroacetyl-L-ornithine (NCAO), a competitive inhibitor of ornithine decarboxylase, an enzyme which is key in the biosynthesis of polyamines (PAs).
METHODS: The cytotoxicity of NCAO was evaluated by MTT in cell culture. The inhibitory effect of CHIKV replication by NCAO was evaluated in Vero and C6/36 cells. The intracellular polyamines were quantified by HPLC in CHIKV-infected cells. We evaluated the yield of CHIKV in titres via the addition of PAs in Vero, C6/36 cells and human fibroblast BJ treated with NCAO.
RESULTS: We found that NCAO inhibits the replication of CHIKV in Vero and C6/36 cells in a dose-dependent manner, causing a decrease in the PFU/mL of at least 4 logarithms (p < 0.01) in both cell lines. Viral yields were restored by the addition of exogenous polyamines, mainly putrescine. The HPLC analyses showed that NCAO decreases the content of intracellular PAs, even though it is predominantly spermidines and spermines which are present in infected cells. Inhibition of CHIKV replication was observed in human fibroblast BJ treated with 100 μM NCAO 24 h before and 48 h after the infection at a MOI 1.
CONCLUSIONS: NCAO inhibits CHIKV replication by depleting the intracellular polyamines in Vero, C6/36 cells and human fibroblast BJ, suggesting that this compound is a possible antiviral agent for CHIKV.

Keywords:  Chikungunya ; Chloroacetylornithine; Inhibition; Polyamines; Replication

DOI:  https://doi.org/10.1177/13596535231155263
bioRxiv. 2023 Jan 04. pii: 2023.01.04.522626. [Epub ahead of print]

Extensive diversity in RNA termination and regulation revealed by transcriptome mapping for the Lyme pathogen B. burgdorferi.

Emily Petroni, Caroline Esnault, Daniel Tetreault, Ryan K Dale, Gisela Storz, Philip P Adams.

Transcription termination is an essential and dynamic process that can tune gene expression in response to diverse molecular signals. Yet, the genomic positions, molecular mechanisms, and regulatory consequences of termination have only been studied thoroughly in model bacteria. We employed complementary RNA-seq approaches to map RNA ends for the transcriptome of the spirochete Borrelia burgdorferi - the etiological agent of Lyme disease. By systematically mapping B. burgdorferi RNA ends at single nucleotide resolution, we delineated complex gene arrangements and operons and mapped untranslated regions (UTRs) and small RNAs (sRNAs). We experimentally tested modes of B. burgdorferi transcription termination and compared our findings to observations in E. coli , P. aeruginosa , and B. subtilis . We discovered 63% of B. burgdorferi RNA 3' ends map upstream or internal to open reading frames (ORFs), suggesting novel mechanisms of regulation. Northern analysis confirmed the presence of stable 5' derived RNAs from mRNAs encoding gene products involved in the unique infectious cycle of B. burgdorferi . We suggest these RNAs resulted from premature termination and regulatory events, including forms of cis- acting regulation. For example, we documented that the polyamine spermidine globally influences the generation of truncated mRNAs. In one case, we showed that high spermidine concentrations increased levels of RNA fragments derived from an mRNA encoding a spermidine import system, with a concomitant decrease in levels of the full- length mRNA. Collectively, our findings revealed new insight into transcription termination and uncovered an abundance of potential RNA regulators.

DOI: https://doi.org/10.1101/2023.01.04.522626
Front Mol Biosci. 2023 ;10 1073770

Identification of a polyamine-related signature and six novel prognostic biomarkers in oral squamous cell carcinoma.

Jiezhang Tang, Xuechen Wu, Bo Cheng, Yajie Lu.

  Elevated polyamine levels are required for tumor transformation and development; however, expression patterns of polyamines and their diagnostic potential have not been investigated in oral squamous cell carcinoma (OSCC), and its impact on prognosis has yet to be determined. A total of 440 OSCC samples and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Consensus clustering was conducted to classify OSCC patients into two subgroups based on the expression of the 17 polyamine regulators. Polyamine-related differentially expressed genes (PARDEGs) among distinct polyamine clusters were determined. To create a prognostic model, PARDEGs were examined in the training cohorts using univariate-Lasso-multivariate Cox regression analyses. Six prognostic genes, namely, "CKS2," "RIMS3," "TRAC," "FMOD," CALML5," and "SPINK7," were identified and applied to develop a predictive model for OSCC. According to the median risk score, the patients were split into high-risk and low-risk groups. The predictive performance of the six gene models was proven by the ROC curve analysis of the training and validation cohorts. Kaplan-Meier curves revealed that the high-risk group had poorer prognosis. Furthermore, the low-risk group was more susceptible to four chemotherapy drugs according to the IC50 of the samples computed by the "pRRophetic" package. The correlation between the risk scores and the proportion of immune cells was calculated. Meanwhile, the tumor mutational burden (TMB) value of the high-risk group was higher. Real-time quantitative polymerase chain reaction was applied to verify the genes constructing the model. The possible connections of the six genes with various immune cell infiltration and therapeutic markers were anticipated. In conclusion, we identified a polyamine-related prognostic signature, and six novel biomarkers in OSCC, which may provide insights to identify new treatment targets for OSCC.

Keywords:  The Cancer Genome Atlas; bioinformatics analyses; immune infiltration; oral squamous cell carcinoma; polyamines; prognostic model

DOI:  https://doi.org/10.3389/fmolb.2023.1073770
Res Sq. 2023 Jan 10. pii: rs.3.rs-2320717. [Epub ahead of print]

Post-fast refeeding enhances intestinal stem cell-mediated regeneration and tumourigenesis through mTORC1-dependent polyamine synthesis.

Shinya Imada, Heaji Shin, Saleh Khawaled, Sven Meckelmann, Charles Whittaker, Renan Correa, Dikshant Pradhan, Gizem Calibasi, Luiza Nascentes Nascentes, Gabriele Allies, Pia Wittenhofer, Oliver Schmitz, Jatin Roper, Marco Vinolo, Chia-Wei Cheng, Alpaslan Tasdogan, Ã-Mer Yilmaz.

For more than a century, fasting regimens have improved health, lifespan, and tissue regeneration in diverse organisms, including humans. However, how fasting and post-fast refeeding impact adult stem cells and tumour formation has yet to be explored in depth. Here, we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation: Post-fast refeeding augments the regenerative capacity of Lgr5+ intestinal stem cells (ISCs), and loss of the tumour suppressor Apc in ISCs under post-fast refeeding leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum (AL) fed states. This demonstrates that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust induction of mTORC1 in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production, or protein synthesis abrogates the regenerative or tumourigenic effects of post-fast refeeding. Thus, fast-refeeding cycles must be carefully considered when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst not only in stem cell-driven regeneration but also in tumourigenicity.

DOI: https://doi.org/10.21203/rs.3.rs-2320717/v1
Funct Plant Biol. 2023 Feb;50(2): i-iv

Polyamines and nitric oxide crosstalk in plant development and abiotic stress tolerance.

Durgesh K Tripathi, Javaid A Bhat, Parvaiz Ahmad, Suleyman I Allakhverdiev.

Polyamines (PAs) and nitric oxide (NO) are crucial signalling molecules that exhibit a promising role in improving stress tolerance in plants, maintaining their growth and development. They act as protecting agents for plants through activation of stress adaptation strategies such as membrane stabilisation, acid neutralisation and suppression of ROS generation. NO interacts with PAs during several developmental processes and stress responses. External supplementation of PAs to plants is also reported to cause an increase in NO content. However, it is unclear whether PAs promote synthesis of NO by either as substrates, cofactors, or signals. Impact of NO on synthesis of PAs has been also reported in some studies, yet the exact governing mechanisms of the interrelation between NO and PAs is currently obscure. Understanding the crosstalk between PAs and NO during growth and stress condition in plants can aid in providing better tolerance to plants against stressful environment.

DOI: https://doi.org/10.1071/FP22170
Anticancer Drugs. 2022 Nov 21.

Circular RNA circ_0003028 regulates cell development through modulating miR-498/ornithine decarboxylase 1 axis in hepatocellular carcinoma.

Tao Zhang, Qikai Sun, Chao Shen, Yeben Qian.

Circular RNA has been revealed to participate in multiple biological functions and contribute to various diseases' progression. This study aims to clarify the role of circ_0003028 and its potential molecular mechanism in hepatocellular carcinoma (HCC). The levels of circ_0003028, miR-498, and ornithine decarboxylase 1 (ODC1) mRNA were examined by quantitative real-time PCR. The cell proliferation ability was detected via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, colony formation, and 5-ethynyl-2'-deoxyuridine assays. The apoptotic rate was evaluated through flow cytometry. The migration and invasion capacity was tested by using wound healing assay and transwell assay. The protein levels of E-cadherin, N-cadherin, and vimentin were measured by western blot assay. The ceRNA regulatory mechanism of circ_0003028 was observed via dual-luciferase reporter and RNA pull-down assays. The mice xenograft models were constructed to confirm the oncogenicity of circ_0003028 in HCC in vivo. Circ_0003028 and ODC1 were upregulated, whereas miR-498 was downregulated in HCC tissues and cells. Circ_0003028 knockdown inhibited cell proliferation and metastasis, and promoted apoptosis. MiR-498 was a direct target of circ_0003028, and inhibition of miR-498 reversed the inhibitory effect of circ_0003028 silencing on HCC progression. Moreover, ODC1 was a direct target of miR-498 and ODC1 overexpression abated the anticancer roles of miR-498 in HCC. Additionally, circ_0003028 regulated ODC1 expression by sponging miR-498. Finally, we found that circ_0003028 could induce epithelial-mesenchymal transition of HCC cells by exosome pathway. In brief, the results demonstrated that circ_0003028 exerted tumourigenicity roles via miR-498/ODC1 signaling axis, providing a promising biomarker and therapeutic target for HCC.

DOI: https://doi.org/10.1097/CAD.0000000000001457
Immunity. 2023 Jan 26. pii: S1074-7613(23)00011-0. [Epub ahead of print]

Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS.

Lina Wang, Siru Li, Kai Wang, Na Wang, Qiaoling Liu, Zhen Sun, Li Wang, Lulu Wang, Quentin Liu, Chengli Song, Qingkai Yang.

  Self-nonself discrimination is vital for the immune system to mount responses against pathogens while maintaining tolerance toward the host and innocuous commensals during homeostasis. Here, we investigated how indiscriminate DNA sensors, such as cyclic GMP-AMP synthase (cGAS), make this self-nonself distinction. Screening of a small-molecule library revealed that spermine, a well-known DNA condenser associated with viral DNA, markedly elevates cGAS activation. Mechanistically, spermine condenses DNA to enhance and stabilize cGAS-DNA binding, optimizing cGAS and downstream antiviral signaling. Spermine promotes condensation of viral, but not host nucleosome, DNA. Deletion of viral DNA-associated spermine, by propagating virus in spermine-deficient cells, reduced cGAS activation. Spermine depletion subsequently attenuated cGAS-mediated antiviral and anticancer immunity. Collectively, our results reveal a pathogenic DNA-associated molecular pattern that facilitates nonself recognition, linking metabolism and pathogen recognition.

Keywords:  DNA condensation; DNA sensing; cGAS; phase separation

DOI:  https://doi.org/10.1016/j.immuni.2023.01.001