Nat Cancer. 2024 Feb 27. doi: 10.1038/s43018-024-00736-x. Online ahead of print.

ABSTRACT

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

PMID:38413714 | DOI:10.1038/s43018-024-00736-x

Sci Rep. 2024 Feb 27;14(1):4723. doi: 10.1038/s41598-024-55332-x.

ABSTRACT

Z-DNA, a well-known non-canonical form of DNA involved in gene regulation, is often found in gene promoters. Transposable elements (TEs), which make up 45% of the human genome, can move from one location to another within the genome. TEs play various biological roles in host organisms, and like Z-DNA, can influence transcriptional regulation near promoter regions. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play a critical role in the regulation of gene expression. Although TEs can generate Z-DNA and miRNAs can bind to Z-DNA, how these factors affect gene transcription has yet to be elucidated. Here, we identified potential Z-DNA forming sequence (ZFS), including TE-derived ZFS, in the promoter of prostaglandin reductase 1 (PTGR1) by data analysis. The transcriptional activity of these ZFS in PTGR1 was confirmed using dual-luciferase reporter assays. In addition, we discovered a novel ZFS-binding miRNA (miR-6867-5p) that suppressed PTGR1 expression by targeting to ZFS. In conclusion, these findings suggest that ZFS, including TE-derived ZFS, can regulate PTGR1 gene expression and that miR-6867-5p can suppress PTGR1 by interacting with ZFS.

PMID:38413664 | DOI:10.1038/s41598-024-55332-x

Nat Commun. 2024 Feb 27;15(1):1794. doi: 10.1038/s41467-024-46036-x.

ABSTRACT

Ex vivo cellular system that accurately replicates sickle cell disease and β-thalassemia characteristics is a highly sought-after goal in the field of erythroid biology. In this study, we present the generation of erythroid progenitor lines with sickle cell disease and β-thalassemia mutation using CRISPR/Cas9. The disease cellular models exhibit similar differentiation profiles, globin expression and proteome dynamics as patient-derived hematopoietic stem/progenitor cells. Additionally, these cellular models recapitulate pathological conditions associated with both the diseases. Hydroxyurea and pomalidomide treatment enhanced fetal hemoglobin levels. Notably, we introduce a therapeutic strategy for the above diseases by recapitulating the HPFH3 genotype, which reactivates fetal hemoglobin levels and rescues the disease phenotypes, thus making these lines a valuable platform for studying and developing new therapeutic strategies. Altogether, we demonstrate our disease cellular systems are physiologically relevant and could prove to be indispensable tools for disease modeling, drug screenings and cell and gene therapy-based applications.

PMID:38413594 | DOI:10.1038/s41467-024-46036-x

Am J Trop Med Hyg. 2024 Feb 27:tpmd230652. doi: 10.4269/ajtmh.23-0652. Online ahead of print.

ABSTRACT

Chagas disease (CD) is caused by the protozoan Trypanosoma cruzi, which leads to a spectrum of clinical presentations that range from asymptomatic to severe cardiac involvement. The host immune response plays a pivotal role in disease progression. Ig isotypes may contribute to disease pathogenesis. Investigating these components can provide insights into the immunopathogenic mechanisms underlying CD. This cross-sectional study aims to establish a correlation between the Ig profile of individuals infected with T. cruzi with the clinical forms of chronic CD. Serum samples were collected from partner institutions in different states of Brazil. Individuals diagnosed with chronic CD were categorized based on the clinical form of the disease. The indirect ELISA method using the recombinant chimeric Molecular Biology Institute of Paraná membrane protein 8.4 as the antigen was used to determine the Ig profile, including total IgG, IgG1, IgG2, IgG3, and IgG4. Ninety-seven serum samples from patients classified as negative (NEG, n = 38), indeterminate (IND, n = 24), mild cardiac (MC, n = 20), and severe cardiac (SC, n = 15) forms were analyzed. IgG1 exhibited greater levels compared with the other isotypes, showing a significant difference between the MC and IND groups. IgG3 levels were greater in individuals from the MC group compared with the SC group. IgG1 and IgG3 isotypes can serve as biomarkers to evaluate the progression of CD because they exhibit variations across clinical groups. Additional longitudinal studies are necessary to explore the relationship between antibody kinetics and the development of tissue damage.

PMID:38412539 | DOI:10.4269/ajtmh.23-0652

Plant Physiol. 2024 Feb 27:kiae078. doi: 10.1093/plphys/kiae078. Online ahead of print.

ABSTRACT

Poplar (Populus) is a well-established model system for tree genomics and molecular breeding, and hybrid poplar is widely used in forest plantations. However, distinguishing its diploid homologous chromosomes is difficult, complicating advanced functional studies on specific alleles. In this study, we applied a trio-binning design and PacBio High-Fidelity long-read sequencing to obtain haplotype-phased telomere-to-telomere genome assemblies for the two parents of the well-studied F1 hybrid "84K" (Populus alba × P. tremula var. glandulosa). Almost all chromosomes, including the telomeres and centromeres, were completely assembled for each haplotype subgenome apart from two small gaps on one chromosome. By incorporating information from these haplotype assemblies and extensive RNA-seq data, we analyzed gene expression patterns between the two subgenomes and alleles. Transcription bias at the subgenome level was not uncovered, but extensive expression differences were detected between alleles. We developed machine-learning (ML) models to predict allele-specific expression (ASE) with high accuracy and identified underlying genome features most highly influencing ASE. One of our models with 15 predictor variables achieved 77% accuracy on the training set and 74% accuracy on the testing set. ML models identified gene body CHG methylation, sequence divergence, and transposon occupancy both upstream and downstream of alleles as important factors for ASE. Our haplotype-phased genome assemblies and ML strategy highlight an avenue for functional studies in Populus and provide additional tools for studying ASE and heterosis in hybrids.

PMID:38412470 | DOI:10.1093/plphys/kiae078

Sci Signal. 2024 Feb 27;17(825):eadf2670. doi: 10.1126/scisignal.adf2670. Epub 2024 Feb 27.

ABSTRACT

More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes in breast cancer cell lines. A growth inhibition screen with 288 cancer cell lines confirmed that INY-05-040 had a substantially higher potency than our first-generation AKT degrader (INY-03-041), with both compounds outperforming catalytic AKT inhibition by GDC-0068. Using multiomic profiling and causal network integration in breast cancer cells, we demonstrated that the enhanced efficacy of INY-05-040 was associated with sustained suppression of AKT signaling, which was followed by induction of the stress mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Together, our study presents a framework for mapping the network-wide signaling effects of therapeutically relevant compounds and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling.

PMID:38412255 | DOI:10.1126/scisignal.adf2670

Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2318743121. doi: 10.1073/pnas.2318743121. Epub 2024 Feb 27.

ABSTRACT

Protein dynamics form a critical bridge between protein structure and function, yet the impact of evolution on ultrafast processes inside proteins remains enigmatic. This study delves deep into nanosecond-scale protein dynamics of a structurally and functionally conserved protein across species separated by almost a billion years, investigating ten homologs in complex with their ligand. By inducing a photo-triggered destabilization of the ligand inside the binding pocket, we resolved distinct kinetic footprints for each homolog via transient infrared spectroscopy. Strikingly, we found a cascade of rearrangements within the protein complex which manifest in time points of increased dynamic activity conserved over hundreds of millions of years within a narrow window. Among these processes, one displays a subtle temporal shift correlating with evolutionary divergence, suggesting reduced selective pressure in the past. Our study not only uncovers the impact of evolution on molecular processes in a specific case, but has also the potential to initiate a field of scientific inquiry within molecular paleontology, where species are compared and classified based on the rapid pace of protein dynamic processes; a field which connects the shortest conceivable time scale in living matter (10[Formula: see text] s) with the largest ones (10[Formula: see text] s).

PMID:38412135 | DOI:10.1073/pnas.2318743121

mBio. 2024 Feb 27:e0336023. doi: 10.1128/mbio.03360-23. Online ahead of print.

ABSTRACT

SARS-CoV-2 infects both the upper and lower respiratory tracts, which are characterized by different temperatures (33°C and 37°C, respectively). In addition, fever is a common COVID-19 symptom. SARS-CoV-2 has been shown to replicate more efficiently at low temperatures, but the effect of temperature on different viral proteins remains poorly understood. Here, we investigate how temperature affects the SARS-CoV-2 spike function and evolution. We first observed that increasing temperature from 33°C to 37°C or 39°C increased spike-mediated cell-cell fusion. We then experimentally evolved a recombinant vesicular stomatitis virus expressing the SARS-CoV-2 spike at these different temperatures. We found that spike-mediated cell-cell fusion was maintained during evolution at 39°C but was lost in a high proportion of viruses that evolved at 33°C or 37°C. Consistently, sequencing of the spikes evolved at 33°C or 37°C revealed the accumulation of mutations around the furin cleavage site, a region that determines cell-cell fusion, whereas this did not occur in spikes evolved at 39°C. Finally, using site-directed mutagenesis, we found that disruption of the furin cleavage site had a temperature-dependent effect on spike-induced cell-cell fusion and viral fitness. Our results suggest that variations in body temperature may affect the activity and diversification of the SARS-CoV-2 spike.IMPORTANCEWhen it infects humans, SARS-CoV-2 is exposed to different temperatures (e.g., replication site and fever). Temperature has been shown to strongly impact SARS-CoV-2 replication, but how it affects the activity and evolution of the spike protein remains poorly understood. Here, we first show that high temperatures increase the SARS-CoV-2 spike fusogenicity. Then, we demonstrate that the evolution of the spike activity and variants depends on temperature. Finally, we show that the functional effect of specific spike mutations is temperature-dependent. Overall, our results suggest that temperature may be a factor influencing the activity and adaptation of the SARS-CoV-2 spike in vivo, which will help understanding viral tropism, pathogenesis, and evolution.

PMID:38411986 | DOI:10.1128/mbio.03360-23

Methods Mol Biol. 2024;2772:261-272. doi: 10.1007/978-1-0716-3710-4_19.

ABSTRACT

Proteotoxic stress of the endoplasmic reticulum (ER) is a potentially lethal condition that ensues when the biosynthetic capacity of the ER is overwhelmed. A sophisticated and largely conserved signaling, known as the unfolded protein response (UPR), is designed to monitor and alleviate ER stress. In plants, the emerging picture of gene regulation by the UPR now appears to be more complex than ever before, requiring multi-omics-enabled network-level approaches to be untangled. In the past decade, with an increasing access and decreasing costs of next-generation sequencing (NGS) and high-throughput protein-DNA interaction (PDI) screening technologies, multitudes of global molecular measurements, known as omics, have been generated and analyzed by the research community to investigate the complex gene regulation of plant UPR. In this chapter, we present a comprehensive catalog of omics resources at different molecular levels (transcriptomes, protein-DNA interactomes, and networks) along with the introduction of key concepts in experimental and computational tools in data generation and analyses. This chapter will serve as a starting point for both experimentalists and bioinformaticians to explore diverse omics datasets for their biological questions in the plant UPR, with likely applications also in other species for conserved mechanisms.

PMID:38411820 | DOI:10.1007/978-1-0716-3710-4_19

Methods Mol Biol. 2024;2772:249-260. doi: 10.1007/978-1-0716-3710-4_18.

ABSTRACT

The cereal endosperm is a complex structure comprising distinct cell types, characterized by specialized organelles for the accumulation of storage proteins. Protein trafficking in these cells is complicated by the presence of several different storage organelles including protein bodies (PBs) derived from the endoplasmic reticulum (ER) and dynamic protein storage vacuoles (PSVs). In addition, trafficking may follow a number of different routes depending on developmental stage, showing that the endomembrane system is capable of massive reorganization. Thus, developmental sequences involve progressive changes of the endomembrane system of endosperm tissue and are characterized by a high structural plasticity and endosomal activity.Given the technical dexterity required to access endosperm tissue and study subcellular structures and SSP trafficking in cereal seeds, static images are the state of the art providing a bulk of information concerning the cellular composition of seed tissue. In view of the highly dynamic endomembrane system in cereal endosperm cells, it is reasonable to expect that live cell imaging will help to characterize the spatial and temporal changes of the endomembrane system. The high resolution achieved with electron microscopy perfectly complements the live cell imaging.We therefore established an imaging platform for TEM as well as for live cell imaging. Here, we describe the preparation of different cereal seed tissues for live cell imaging concomitant with immunolocalization studies and ultrastructure.

PMID:38411819 | DOI:10.1007/978-1-0716-3710-4_18

Mol Biol Evol. 2024 Feb 27:msae042. doi: 10.1093/molbev/msae042. Online ahead of print.

ABSTRACT

Evolutionary epigenomics and, more generally, evolutionary functional-genomics, are emerging fields that study how non-DNA-encoded alterations in gene expression regulation are an important form of plasticity and adaptation. Previous evidence analysing plants' comparative functional genomics has mostly focused on comparing same assay-matched experiments, missing the power of heterogeneous datasets for conservation inference. To fill this gap, we developed PlantFUN(ctional)CO(nservation) database, which is constituted by several tools and two main resources: inter-species chromatin states and functional genomics conservation scores, presented and analysed in this work for three well-established plant models (Arabidopsis thaliana, Oryza sativa and Zea mays). Overall, PlantFUNCO elucidated evolutionary information in terms of cross-species functional agreement. Therefore, providing a new complementary comparative-genomics source for assessing evolutionary studies. To illustrate the potential applications of this database, we replicated two previously published models predicting genetic redundancy in A. thaliana and found that chromatin states are a determinant of paralogs degree of functional divergence. These predictions were validated based on the phenotypes of mitochondrial alternative oxidase knockout mutants under two different stressors. Taking all the above into account, PlantFUNCO aim to leverage data diversity and extrapolate molecular mechanisms findings from different model organisms to determine the extent of functional conservation, thus, deepening our understanding of how plants epigenome and functional non-coding genome have evolved. PlantFUNCO is available at https://rocesv.github.io/PlantFUNCO.

PMID:38411627 | DOI:10.1093/molbev/msae042

Elife. 2024 Feb 27;12:RP86823. doi: 10.7554/eLife.86823.

ABSTRACT

Eukaryotes respond to secreted metabolites from the microbiome. However, little is known about the effects of exposure to volatiles emitted by microbes or in the environment that we are exposed to over longer durations. Using Drosophila melanogaster, we evaluated a yeast-emitted volatile, diacetyl, found at high levels around fermenting fruits where they spend long periods of time. Exposure to the diacetyl molecules in headspace alters gene expression in the antenna. In vitro experiments demonstrated that diacetyl and structurally related volatiles inhibited conserved histone deacetylases (HDACs), increased histone-H3K9 acetylation in human cells, and caused changes in gene expression in both Drosophila and mice. Diacetyl crosses the blood-brain barrier and exposure caused modulation of gene expression in the mouse brain, therefore showing potential as a neuro-therapeutic. Using two separate disease models previously known to be responsive to HDAC inhibitors, we evaluated the physiological effects of volatile exposure. Diacetyl exposure halted proliferation of a neuroblastoma cell line in culture. Exposure to diacetyl vapors slowed progression of neurodegeneration in a Drosophila model for Huntington's disease. These changes strongly suggest that certain volatiles in the surroundings can have profound effects on histone acetylation, gene expression, and physiology in animals.

PMID:38411140 | DOI:10.7554/eLife.86823

Microbiol Resour Announc. 2024 Feb 27:e0118523. doi: 10.1128/mra.01185-23. Online ahead of print.

ABSTRACT

The genomes of 21 Pedobacter strains isolated from the European salamander Salamandra salamandra and different Madagascan frog species were sequenced using Illumina sequencing. Here, we report their draft genome sequences (~4.7-7.2 Mbp in size) to allow comparative genomics and taxonomic assignment of these strains.

PMID:38411067 | DOI:10.1128/mra.01185-23

Nat Rev Methods Primers. 2021;1:10. doi: 10.1038/s43586-020-00008-9. Epub 2021 Jan 21.

ABSTRACT

Chromatin accessibility, or the physical access to chromatinized DNA, is a widely studied characteristic of the eukaryotic genome. As active regulatory DNA elements are generally 'accessible', the genome-wide profiling of chromatin accessibility can be used to identify candidate regulatory genomic regions in a tissue or cell type. Multiple biochemical methods have been developed to profile chromatin accessibility, both in bulk and at the single-cell level. Depending on the method, enzymatic cleavage, transposition or DNA methyltransferases are used, followed by high-throughput sequencing, providing a view of genome-wide chromatin accessibility. In this Primer, we discuss these biochemical methods, as well as bioinformatics tools for analysing and interpreting the generated data, and insights into the key regulators underlying developmental, evolutionary and disease processes. We outline standards for data quality, reproducibility and deposition used by the genomics community. Although chromatin accessibility profiling is invaluable to study gene regulation, alone it provides only a partial view of this complex process. Orthogonal assays facilitate the interpretation of accessible regions with respect to enhancer-promoter proximity, functional transcription factor binding and regulatory function. We envision that technological improvements including single-molecule, multi-omics and spatial methods will bring further insight into the secrets of genome regulation.

PMID:38410680 | PMC:PMC10895463 | DOI:10.1038/s43586-020-00008-9

Int J Biol Markers. 2024 Feb 26:3936155241230968. doi: 10.1177/03936155241230968. Online ahead of print.

ABSTRACT

PURPOSE: Ultraviolet radiation causes skin cancer, but the exact mechanism by which it occurs and the most effective methods of intervention to prevent it are yet unknown. For this purpose, our study will use bioinformatics and systems biology approaches to discover potential biomarkers of skin cancer for early diagnosis and prevention of disease with applicable clinical treatments.

METHODS: This study compared gene expression and protein levels in ultraviolet-mediated cultured keratinocytes and adjacent normal skin tissue using RNA sequencing data from the National Center for Biotechnology Information-Gene Expression Omnibus (NCBI-GEO) database. Then, pathway analysis was employed with a selection of hub genes from the protein-protein interaction (PPI) network and the survival and expression profiles. Finally, potential clinical biomarkers were validated by receiver operating characteristic (ROC) curve analysis.

RESULTS: We identified 32 shared differentially expressed genes (DEGs) by analyzing three different subsets of the GSE85443 dataset. Skin cancer development is related to the control of several DEGs through cyclin-dependent protein serine/threonine kinase activity, cell cycle regulation, and activation of the NIMA kinase pathways. The cytoHubba plugin in Cytoscape identified 12 hub genes from PPI; among these 3 DEGs, namely, AURKA, CDK4, and PLK1 were significantly associated with survival (P < 0.05) and highly expressed in skin cancer tissues. For validation purposes, ROC curve analysis indicated two biomarkers: AURKA (area under the curve (AUC) value = 0.8) and PLK1 (AUC value = 0.7), which were in an acceptable range.

CONCLUSIONS: Further translational research, including clinical experiments, teratogenicity tests, and in-vitro or in-vivo studies, will be performed to evaluate the expression of these identified biomarkers regarding the prognosis of skin cancer patients.

PMID:38410032 | DOI:10.1177/03936155241230968

J Cardiovasc Transl Res. 2024 Feb 26. doi: 10.1007/s12265-024-10501-1. Online ahead of print.

ABSTRACT

In-hospital mortality associated with cardiogenic shock (CS) remains high despite the use of percutaneous assist devices. We sought to determine whether support with VA-ECMO or Impella in patients with CS alters specific components of the plasma proteome. Plasma samples were collected before device implantation and 72 h after initiation of support in 11 CS patients receiving ECMO or Impella. SOMAscan was used to detect 1305 circulating proteins. Sixty-seven proteins were changed after ECMO (18 upregulated and 49 downregulated, p < 0.05), 38 after Impella (10 upregulated and 28 downregulated, p < 0.05), and only eight proteins were commonly affected. Despite minimal protein overlap, both devices were associated with markers of reduced inflammation and increased apoptosis of inflammatory cells. In summary, ECMO and Impella are associated with reduced expression of inflammatory markers and increased markers of inflammatory cell death. These circulating proteins may serve as novel targets of therapy or biomarkers to tailor AMCS use.

PMID:38409476 | DOI:10.1007/s12265-024-10501-1

Sci Rep. 2024 Feb 26;14(1):4695. doi: 10.1038/s41598-024-55211-5.

ABSTRACT

Insect feeding structures, such as mandibles, interact with the ingesta (food or/and substrate) and can be adapted in morphology, composition of material and mechanical properties. The foraging on abrasive ingesta, as on algae covering rocks, is particularly challenging because the mandibles will be prone to wear and structural failure, thus suggesting the presence of mandibular adaptations to accompany this feeding behavior. Adaptations to this are well studied in the mouthparts of molluscs and sea urchins, but for insects there are large gaps in our knowledge. In this study, we investigated the mandibles of a grazing insect, the larvae of the trichopteran Glossosoma boltoni. Using scanning electron microscopy, wear was documented on the mandibles. The highest degree was identified on the medial surface of the sharp mandible tip. Using nanoindentation, the mechanical properties, such as hardness and Young's modulus, of the medial and lateral mandible cuticles were tested. We found, that the medial cuticle of the tip was significantly softer and more flexible than the lateral one. These findings indicate that a self-sharpening mechanism is present in the mandibles of this species, since the softer medial cuticle is probably abraded faster than the harder lateral one, leading to sharp mandible tips. To investigate the origins of these properties, we visualized the degree of tanning by confocal laser scanning microscopy. The autofluorescence signal related to the mechanical property gradients. The presence of transition and alkaline earth metals by energy dispersive X-ray spectroscopy was also tested. We found Ca, Cl, Cu, Fe, K, Mg, Mn, P, S, Si, and Zn in the cuticle, but the content was very low and did not correlate with the mechanical property values.

PMID:38409429 | DOI:10.1038/s41598-024-55211-5

Commun Biol. 2024 Feb 26;7(1):234. doi: 10.1038/s42003-024-05810-9.

NO ABSTRACT

PMID:38409374 | DOI:10.1038/s42003-024-05810-9

Sci Rep. 2024 Feb 26;14(1):7334. doi: 10.1038/s41598-023-33629-7.

ABSTRACT

Exposure to cosmic ionizing radiation is an innate risk of the spaceflight environment that can cause DNA damage and altered cellular function. In astronauts, longitudinal monitoring of physiological systems and interactions between these systems are important to consider for mitigation strategies. In addition, assessments of sex-specific biological responses in the unique environment of spaceflight are vital to support future exploration missions that include both females and males. Here we assessed sex-specific, multi-system immune and endocrine responses to simulated cosmic radiation. For this, 24-week-old, male and female C57Bl/6J mice were exposed to simplified five-ion, space-relevant galactic cosmic ray (GCRsim) radiation at 15 and 50 cGy, to simulate predicted radiation exposures that would be experienced during lunar and Martian missions, respectively. Blood and adrenal tissues were collected at 3- and 14-days post-irradiation for analysis of immune and endocrine biosignatures and pathways. Sexually dimorphic adrenal gland weights and morphology, differential total RNA expression with corresponding gene ontology, and unique immune phenotypes were altered by GCRsim. In brief, this study offers new insights into sexually dimorphic immune and endocrine kinetics following simulated cosmic radiation exposure and highlights the necessity for personalized translational approaches for astronauts during exploration missions.

PMID:38409284 | DOI:10.1038/s41598-023-33629-7

Cell Mol Immunol. 2024 Feb 27. doi: 10.1038/s41423-024-01134-0. Online ahead of print.

ABSTRACT

Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) is poorly understood. Here, we found that the T helper 2 (Th2) cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration, which are essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment. Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs toward an M1-like phenotype, downregulated PD-L1 expression and enhanced antitumor T-cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.

PMID:38409249 | DOI:10.1038/s41423-024-01134-0