Understanding how the homeostasis of cellular size and composition is accomplished by different organisms is an outstanding challenge in biology. For exponentially growing Escherichia coli cells, it ...is long known that the size of cells exhibits a strong positive relation with their growth rates in different nutrient conditions. Here, we characterized cell sizes in a set of orthogonal growth limitations. We report that cell size and mass exhibit positive or negative dependences with growth rate depending on the growth limitation applied. In particular, synthesizing large amounts of “useless” proteins led to an inversion of the canonical, positive relation, with slow growing cells enlarged 7‐ to 8‐fold compared to cells growing at similar rates under nutrient limitation. Strikingly, this increase in cell size was accompanied by a 3‐ to 4‐fold increase in cellular DNA content at slow growth, reaching up to an amount equivalent to ~8 chromosomes per cell. Despite drastic changes in cell mass and macromolecular composition, cellular dry mass density remained constant. Our findings reveal an important role of protein synthesis in cell division control.
Synopsis
Protein overexpression inverts the well‐known positive relation of cell size and DNA content with growth rate under nutrient limitation, resulting in huge, slowly growing cells with high DNA content, but with remarkably constant cellular dry mass density.
Protein overexpression leads to an inverted growth rate dependence of cell size, with slow growing cells being even larger than the fastest growing wild‐type cells cultured in rich media.
Decoupled from growth rate, changes in cell size are accompanied by comparable changes in cellular DNA content.
Despite profound changes in cell size and macromolecular composition, cellular dry mass density remains remarkably constant, as protein overexpression does not result in molecular crowding.
Protein overexpression inverts the well‐known positive relation of cell size and DNA content with growth rate under nutrient limitation, resulting in huge, slowly growing cells with high DNA content, but with remarkably constant cellular dry mass density.
Glucose‐6‐phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular ...reductant. G6PD deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. Here, we show that G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re‐expression of wild‐type G6PD, but not the K403 acetylation mimetic mutant, rescues cells from oxidative injury. Moreover, we show that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2‐dependent manner. The SIRT2‐mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. We also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.
Synopsis
The pentose phosphate pathway plays an important role in the oxidative stress response by supplying the reductant NADPH. SIRT2‐mediated deacetylation and activation of the glucose‐6‐phosphate dehydrogenase, the rate‐limiting enzyme in this pathway, stimulates the production of cytosolic NADPH to counteract oxidative damage.
K403 acetylation decreases G6PD activity by inhibiting dimer formation.
SIRT2 and KAT9/ELP3 regulate G6PD K403 acetylation.
Regulation of G6PD K403 acetylation modulates NADPH homeostasis and cell survival during oxidative stress.
Following oxidative stress, production of the reductant NADPH via the pentose phosphate pathway is stimulated by SIRT2‐mediated deacetylation and activation of G6PD.
Problem-solving ability is an essential part of daily life. Thus, curiosity and a thirst for knowledge should be cultivated in students to help them develop problem solving and independent thinking ...skills. Along with positive attitudes and an active disposition, these abilities are needed to solve problems throughout the lifespan and develop -confidence. To achieve educational objectives in the context of globalization, creative ability is necessary for generating competitive advantages. Therefore, creative thinking, critical thinking, and problem-solving ability are important basic competencies needed for future world citizens. Creativity should also be integrated into subject teaching to cultivate students' lifelong learning and a creative attitude toward life. A questionnaire was distributed to 420 students in colleges and universities in Fujian, China. After removing invalid and incomplete responses, 363 copies were found to be valid yielding a response rate of 86%. Findings indicate that the new generation requires high levels of support to develop creativity and integrate diverse subjects such as nature, humanities, and technology. A rich imagination is needed to root creativity in the new generation.
Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells ...rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer.
Display omitted
•Arginine methylation at R248 negatively regulates MDH1 activity•PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization•MDH1 methylation suppresses glutamine metabolism of pancreatic cancer•R248 methylation of MDH1 is downregulated in clinical PDAC samples
Wang et al. show that arginine methylation at R248 of MDH1, which is catalyzed by PRMT4/CARM1, regulates glutamine metabolism and redox homeostasis of pancreatic cancer cells. MDH1 methylation is downregulated in human PDAC samples.
Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)
. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality ...conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC
. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-Kras
; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.
The convenient cross‐coupling of sp2 or sp3 carbons with a specific boron vertex on carborane cage represents significant synthetic values and insurmountable challenges. In this work, we report an ...Rh‐catalyzed reaction between o‐carborane and N‐acyl‐glutarimides to construct various Bcage−C bonds. Under the optimized condition, the removable imine directing group (DG) leads to B(3)− or B(3,6)−C couplings, while the pyridyl DG leads to B(3,5)−Ar coupling. In particular, an unexpected rearrangement of amide reagent is observed in pyridyl directed B(4)−C(sp3) formation. This scalable protocol has many advantages, including easy access, the use of cheap and widely available coupling agents, no requirement of an external ligand, base or oxidant, high efficiency, and a broad substrate scope. Leveraging the RhI dimer and twisted amides, this method enables straightforward access to diversely substituted and therapeutically important carborane derivatives at boron site, and provides a highly valuable vista for carborane‐based drug screening.
Rh catalysis was used to enable cross‐coupling between o‐carborane and twisted amide. A series of regioselective B(3,6)−C, B(3,5)−Ar and B(4)−C(sp3) coupling products have been obtained. The operationally simple reaction gives rise to diverse carboranyl‐fused organic motifs and accommodates late‐stage diversification, which may pave a new way for medicinal investigations.
Sirtuins (SIRTs) are a class of lysine deacylases that regulate cellular metabolism and energy homeostasis. Although sirtuins have been proposed to function in nutrient sensing and signaling, the ...underlying mechanism remains elusive. SIRT7, a histone H3K18‐specific deacetylase, epigenetically controls mitochondria biogenesis, ribosomal biosynthesis, and DNA repair. Here, we report that SIRT7 is methylated at arginine 388 (R388), which inhibits its H3K18 deacetylase activity. Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo. R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization. PRMT6‐induced H3K18 hyperacetylation at SIRT7‐target gene promoter epigenetically promotes mitochondria biogenesis and maintains mitochondria respiration. Moreover, high glucose enhances R388 methylation in mouse fibroblasts and liver tissue. PRMT6 signals glucose availability to SIRT7 in an AMPK‐dependent manner. AMPK induces R388 hypomethylation by disrupting the association between PRMT6 and SIRT7. Together, PRMT6‐induced arginine methylation of SIRT7 coordinates glucose availability with mitochondria biogenesis to maintain energy homeostasis. Our study uncovers the regulatory role of SIRT7 arginine methylation in glucose sensing and mitochondria biogenesis.
Synopsis
PRMT6 methylates and thereby inhibits SIRT7, which epigenetically promotes mitochondria biogenesis and connects it to glucose availability in an AMPK‐dependent manner.
PRMT6 methylates SIRT7 at R388 to suppress its H3K18 deacetylase activity.
PRMT6 modulates SIRT7 methylation in an AMPK‐dependent manner.
SIRT7 methylation connects glucose sensing with mitochondria biogenesis.
PRMT6 methylates and thereby inhibits SIRT7, which epigenetically promotes mitochondria biogenesis and connects it to glucose availability in an AMPK‐dependent manner.
Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer‐induced metabolic ...changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. Recent advances in cancer metabolism shed light on how aberrations in metabolites and metabolic enzymes modify epigenetic programs. The metabolism‐induced recoding of epigenetics in cancer depends strongly on nutrient availability for tumor cells. In this review, we focus on metabolic remodeling of epigenetics in cancer and examine potential mechanisms by which cancer cells integrate nutritional inputs into epigenetic modification.
A large number of genes are necessary for the biosynthesis and activity of the enzyme nitrogenase to carry out the process of biological nitrogen fixation (BNF), which requires large amounts of ATP ...and reducing power. The multiplicity of the genes involved, the oxygen sensitivity of nitrogenase, plus the demand for energy and reducing power, are thought to be major obstacles to engineering BNF into cereal crops. Genes required for nitrogen fixation can be considered as three functional modules encoding electron-transport components (ETCs), proteins required for metal cluster biosynthesis, and the “core” nitrogenase apoenzyme, respectively. Among these modules, the ETC is important for the supply of reducing power. In this work, we have used Escherichia coli as a chassis to study the compatibility between molybdenum and the iron-only nitrogenases with ETC modules from target plant organelles, including chloroplasts, root plastids, and mitochondria. We have replaced an ETC module present in diazotrophic bacteria with genes encoding ferredoxin–NADPH oxidoreductases (FNRs) and their cognate ferredoxin counterparts from plant organelles. We observe that the FNR–ferredoxin module from chloroplasts and root plastids can support the activities of both types of nitrogenase. In contrast, an analogous ETC module from mitochondria could not function in electron transfer to nitrogenase. However, this incompatibility could be overcome with hybrid modules comprising mitochondrial NADPH-dependent adrenodoxin oxidoreductase and the Anabaena ferredoxins FdxH or FdxB. We pinpoint endogenous ETCs from plant organelles as power supplies to support nitrogenase for future engineering of diazotrophy in cereal crops.
Mitochondria harbor the oxidative phosphorylation (OXPHOS) system to sustain cellular respiration. However, the transcriptional regulation of OXPHOS remains largely unexplored. Through the cancer ...genome atlas (TCGA) transcriptome analysis, transcription factor THAP domain‐containing 3 (THAP3) was found to be strongly associated with OXPHOS gene expression. Mechanistically, THAP3 recruited the histone methyltransferase SET and MYND domain‐containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. The levels of THAP3 and SMYD3 were altered by metabolic cues. They collaboratively supported liver cancer cell proliferation and colony formation. In clinical human liver cancer, both of them were overexpressed. THAP3 positively correlated with OXPHOS gene expression. Together, THAP3 cooperates with SMYD3 to epigenetically upregulate cellular respiration and liver cancer cell proliferation.
Through bioinformatic analysis of transcriptomes in the cancer genome atlas (TCGA), we identified a new role for the transcription factor THAP domain‐containing 3 (THAP3) in the expression of oxidative phosphorylation (OXPHOS) genes and mitochondrial respiration. Mechanistically, THAP3 cooperated with the histone methyltransferase SET and MYND domain‐containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. These actions of THAP3 support liver cancer cell proliferation and contribute to tumor development.
PDF
