Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.

The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.

ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.

Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.

Molecular forecasting of domoic acid during a pervasive toxic diatom bloom.

In 2015, the largest recorded harmful algal bloom (HAB) occurred in the Northeast Pacific, causing nearly 100 million dollars in damages to fisheries and killing many protected marine mammals. Dominated by the toxic diatom Pseudo-nitzschia australis, this bloom produced high levels of the neurotoxin domoic acid (DA). Through molecular and transcriptional characterization of 52 near-weekly phytoplankton net-tow samples collected at a bloom hotspot in Monterey Bay, California, we identified active transcription of known DA biosynthesis (dab) genes from the three identified toxigenic species, including P. australis as the primary origin of toxicity. Elevated expression of silicon transporters (sit1) during the bloom supports the previously hypothesized role of dissolved silica (Si) exhaustion in contributing to bloom physiology and toxicity. We find that coexpression of the dabA and sit1 genes serves as a robust predictor of DA one week in advance, potentially enabling the forecasting of DA-producing HABs. We additionally present evidence that low levels of iron could have colimited the diatom population along with low Si. Iron limitation represents an overlooked driver of both toxin production and ecological success of the low-iron-adapted Pseudo-nitzschia genus during the 2015 bloom, and increasing pervasiveness of iron limitation may fuel the escalating magnitude and frequency of toxic Pseudo-nitzschia blooms globally. Our results advance understanding of bloom physiology underlying toxin production, bloom prediction, and the impact of global change on toxic blooms.

Ribosome Hibernation.

Protein synthesis consumes a large fraction of available resources in the cell. When bacteria encounter unfavorable conditions and cease to grow, specialized mechanisms are in place to ensure the overall reduction of costly protein synthesis while maintaining a basal level of translation. A number of ribosome-associated factors are involved in this regulation; some confer an inactive, hibernating state of the ribosome in the form of 70S monomers (RaiA; this and the following are based on Escherichia coli nomenclature) or 100S dimers (RMF and HPF homologs), and others inhibit translation at different stages in the translation cycle (RsfS, YqjD and paralogs, SRA, and EttA). Stationary phase cells therefore exhibit a complex array of different ribosome subpopulations that adjusts the translational capacity of the cell to the encountered conditions and ensures efficient reactivation of translation when conditions improve. Here, we review the current state of research regarding stationary phase-specific translation factors, in particular ribosome hibernation factors and other forms of translational regulation in response to stress conditions.

Assembly, comparative analysis, and utilization of a single haplotype reference genome for soybean.

Cultivar Williams 82 has served as the reference genome for the soybean research community since 2008, but is known to have areas of genomic heterogeneity among different sub-lines. This work provides an updated assembly (version Wm82.a6) derived from a specific sub-line known as Wm82-ISU-01 (seeds available under USDA accession PI 704477). The genome was assembled using Pacific BioSciences HiFi reads and integrated into chromosomes using HiC. The 20 soybean chromosomes assembled into a genome of 1.01Gb, consisting of 36 contigs. The genome annotation identified 48 387 gene models, named in accordance with previous assembly versions Wm82.a2 and Wm82.a4. Comparisons of Wm82.a6 with other near-gapless assemblies of Williams 82 reveal large regions of genomic heterogeneity, including regions of differential introgression from the cultivar Kingwa within approximately 30 Mb and 25 Mb segments on chromosomes 03 and 07, respectively. Additionally, our analysis revealed a previously unknown large (>20 Mb) heterogeneous region in the pericentromeric region of chromosome 12, where Wm82.a6 matches the 'Williams' haplotype while the other two near-gapless assemblies do not match the haplotype of either parent of Williams 82. In addition to the Wm82.a6 assembly, we also assembled the genome of 'Fiskeby III,' a rich resource for abiotic stress resistance genes. A genome comparison of Wm82.a6 with Fiskeby III revealed the nucleotide and structural polymorphisms between the two genomes within a QTL region for iron deficiency chlorosis resistance. The Wm82.a6 and Fiskeby III genomes described here will enhance comparative and functional genomics capacities and applications in the soybean community.

PDR9 allelic variation and MYB63 modulate nutrient-dependent coumarin homeostasis in Arabidopsis.

Plant roots release phytochemicals into the soil environment to influence nutrient availability and uptake. Arabidopsis thaliana roots release phenylpropanoid coumarins in response to iron (Fe) deficiency, likely to enhance Fe uptake and improve plant health. This response requires sufficient phosphorus (P) in the root environment. Nonetheless, the regulatory interplay influencing coumarin production under varying availabilities of Fe and P is not known. Through genome-wide association studies, we have pinpointed the influence of the ABC transporter G family member, PDR9, on coumarin accumulation and trafficking (homeostasis) under combined Fe and P deficiency. We show that genetic variation in the promoter of PDR9 regulates its expression in a manner associated with coumarin production. Furthermore, we find that MYB63 transcription factor controls dedicated coumarin production by regulating both COUMARIN SYNTHASE (COSY) and FERULOYL-CoA 6'-HYDROXYLASE 1 (F6'H1) expression while orchestrating secretion through PDR9 genes under Fe and P combined deficiency. This integrated approach illuminates the intricate connections between nutrient signaling pathways in coumarin response mechanisms.

The Role of FtsH Complexes in the Response to Abiotic Stress in Cyanobacteria.

FtsH proteases (FtsHs) belong to intramembrane ATP-dependent metalloproteases which are widely distributed in eubacteria, mitochondria and chloroplasts. The best-studied roles of FtsH in Escherichia coli include quality control of membrane proteins, regulation of response to heat shock, superoxide stress and viral infection, and control of lipopolysaccharide biosynthesis. While heterotrophic bacteria mostly contain a single indispensable FtsH complex, photosynthetic cyanobacteria usually contain three FtsH complexes: two heterocomplexes and one homocomplex. The essential cytoplasmic FtsH1/3 most probably fulfills a role similar to other bacterial FtsHs, whereas the thylakoid FtsH2/3 heterocomplex and FtsH4 homocomplex appear to maintain the photosynthetic apparatus of cyanobacteria and optimize its functionality. Moreover, recent studies suggest the involvement of all FtsH proteases in a complex response to nutrient stresses. In this review, we aim to comprehensively evaluate the functions of the cyanobacterial FtsHs specifically under stress conditions with emphasis on nutrient deficiency and high irradiance. We also point to various unresolved issues concerning FtsH functions, which deserve further attention.

Preliminary study on the diagnosis of NK stress based on the puncture mechanical characteristics of cucumber stem.

To investigate the relationship between stem puncture mechanical characteristics and NK stress diagnosis, the microstructure, surface morphology, cellulose and lignin content, puncture mechanical characteristics, and epidermal cell morphology of cucumber stems were measured herein. The results indicated that the middle stem, which had a diameter of approximately 7000 µm, was more suitable for puncturing due to its lower amount of epidermal hair, and its gradual regularity in shape. Further, the cucumber stems were protected from puncture damage due to their ability to rapidly heal within 25 h.. The epidermal penetration of the cucumber stems increased with the increase in cellulose and lignin, though cellulose played a more decisive role. The epidermal break distance increased with an increase in N application and decreased with an increase in K+ application, but the change in intercellular space caused by K+ supply was the most critical factor affecting the epidermal break distance. In addition, a decrease in K+ concentration led to a decrease in epidermal brittleness, whereas the factors affecting epidermal toughness were more complex. Finally, we found that although the detection of epidermal brittleness and toughness on nutrient stress was poor under certain treatment, the puncture mechanical characteristics of the stem still had a significant indicative effect on N application rate. Therefore, elucidating of the relationship between the puncture mechanical characteristics of the stems and crop nutritional stress is not only beneficial for promoting stem stress physiology research but also for designing on-site nutritional testing equipment in the future.

How does the neuronal proteostasis network react to cellular cues?

Even though neurons are post-mitotic cells, they still engage in protein synthesis to uphold their cellular content balance, including for organelles, such as the endoplasmic reticulum or mitochondria. Additionally, they expend significant energy on tasks like neurotransmitter production and maintaining redox homeostasis. This cellular homeostasis is upheld through a delicate interplay between mRNA transcription-translation and protein degradative pathways, such as autophagy and proteasome degradation. When faced with cues such as nutrient stress, neurons must adapt by altering their proteome to survive. However, in many neurodegenerative disorders, such as Parkinson's disease, the pathway and processes for coping with cellular stress are impaired. This review explores neuronal proteome adaptation in response to cellular stress, such as nutrient stress, with a focus on proteins associated with autophagy, stress response pathways, and neurotransmitters.

Quantitative Proteomic Analysis of Brassica Napus Reveals Intersections Between Nutrient Deficiency Responses.

Macronutrients such as nitrogen (N), phosphorus (P), potassium (K) and sulphur (S) are critical for plant growth and development. Field-grown canola (Brassica napus L.) is supplemented with fertilizers to maximize plant productivity, while deficiency in these nutrients can cause significant yield loss. A holistic understanding of the interplay between these nutrient deficiency responses in a single study and canola cultivar is thus far lacking, hindering efforts to increase the nutrient use efficiency of this important oil seed crop. To address this, we performed a comparative quantitative proteomic analysis of both shoot and root tissue harvested from soil-grown canola plants experiencing either nitrogen, phosphorus, potassium or sulphur deficiency. Our data provide critically needed insights into the shared and distinct molecular responses to macronutrient deficiencies in canola. Importantly, we find more conserved responses to the four different nutrient deficiencies in canola roots, with more distinct proteome changes in aboveground tissue. Our results establish a foundation for a more comprehensive understanding of the shared and distinct nutrient deficiency response mechanisms of canola plants and pave the way for future breeding efforts.

The genomic basis of nitrogen utilization efficiency and trait plasticity to improve nutrient stress tolerance in cultivated sunflower.

Maintaining crop productivity is challenging as population growth, climate change, and increasing fertilizer costs necessitate expanding crop production to poorer lands whilst reducing inputs. Enhancing crops' nutrient use efficiency is thus an important goal, but requires a better understanding of related traits and their genetic basis. We investigated variation in low nutrient stress tolerance in a diverse panel of cultivated sunflower genotypes grown under high and low nutrient conditions, assessing relative growth rate (RGR) as performance. We assessed variation in traits related to nitrogen utilization efficiency (NUtE), mass allocation, and leaf elemental content. Across genotypes, nutrient limitation generally reduced RGR. Moreover, there was a negative correlation between vigor (RGR in control) and decline in RGR in response to stress. Given this trade-off, we focused on nutrient stress tolerance independent of vigor. This tolerance metric correlated with the change in NUtE, plasticity for a suite of morphological traits, and leaf element content. Genome-wide associations revealed regions associated with variation and plasticity in multiple traits, including two regions with seemingly additive effects on NUtE change. Our results demonstrate potential avenues for improving sunflower nutrient stress tolerance independent of vigor, and highlight specific traits and genomic regions that could play a role in enhancing tolerance.

Using multi-omics to explore the effect of Bacillus velezensis SAAS-63 on resisting nutrient stress in lettuce.

To avoid the unreasonable use of chemical fertilizer, an environmentally friendly means of improving soil fertility is required. This study explored the role of the plant growth-promoting rhizosphere bacteria (PGPR) strain Bacillus velezensis SAAS-63 in improving nutrient stress in lettuce. Compared with no inoculation, B. velezensis SAAS-63 inoculants exhibited significantly increased fresh weight, root length, and shoot height under nutrient deficiency, as well as improved antioxidant activities and proline contents. The exogenous addition of B. velezensis SAAS-63 also significantly increased the accumulation of macroelements and micronutrients in lettuce. To elucidate the resistance mechanisms induced by B. velezensis SAAS-63 under nutrient stress, high-throughput sequencing and multi-omics analysis were performed. Inoculation with B. velezensis SAAS-63 altered the microbial community of the rhizosphere and increased the relative abundances of Streptomyces, Actinoallomurus, Verrucomicrobia, and Chloroflexi. It is worth noting that the inoculant SAAS-63 can affect plant rhizosphere metabolism. The inoculant changed the metabolic flow of phenylpropanoid metabolic pathway under nutrient deficiency and promoted phenylalanine to participate more in the synthesis of lignin precursors and coumarin substances by inhibiting the synthesis of flavone and isoflavone, thus improving plant resistance. This study showed that the addition of inoculant SAAS-63 could help plants recruit microorganisms to decompose and utilize trehalose and re-established the carbon metabolism of the plant rhizosphere. Additionally, microbes were found to be closely related to the accumulation of metabolites based on correlation analysis. The results indicated that the addition of PGPRs has an important role in regulating soil rhizosphere microbes and metabolism, providing valuable information for understanding how PGPRs affect complex biological processes and enhance plant adaptation to nutrient deficiency. KEY POINTS: • Inoculation with SAAS-63 significantly promoted plant growth under nutrient-deficient conditions • Inoculation with SAAS-63 affected rhizosphere microbial diversity and community structure • Inoculation with SAAS-63 affected plant rhizosphere metabolism and induced plants to synthesize substances that resist stress.

Role of microalgae-bacterial consortium in wastewater treatment: A review.

In the global effort to reduce CO2 emissions, the concurrent enhancement of pollutant degradation and reductions in fossil fuel consumption are pivotal aspects of microalgae-mediated wastewater treatment. Clarifying the degradation mechanisms of bacteria and microalgae during pollutant treatment, as well as regulatory biolipid production, could enhance process sustainability. The synergistic and inhibitory relationships between microalgae and bacteria are introduced in this paper. The different stimulators that can regulate microalgal biolipid accumulation are also reviewed. Wastewater treatment technologies that utilize microalgae and bacteria in laboratories and open ponds are described to outline their application in treating heavy metal-containing wastewater, animal husbandry wastewater, pharmaceutical wastewater, and textile dye wastewater. Finally, the major requirements to scale up the cascade utilization of biomass and energy recovery are summarized to improve the development of biological wastewater treatment.

The small GTPase KlRho5 responds to oxidative stress and affects cytokinesis.

Rho5 is the yeast homolog of the human small GTPase Rac1. We characterized the genes encoding Rho5 and the subunits of its dimeric activating guanine-nucleotide-exchange factor (GEF), Dck1 and Lmo1, in the yeast Kluyveromyces lactis. Rapid translocation of the three GFP-tagged components to mitochondria upon oxidative stress and carbon starvation indicate a similar function of KlRho5 in energy metabolism and mitochondrial dynamics as described for its Saccharomyces cerevisiae homolog. Accordingly, Klrho5 deletion mutants are hyper-resistant towards hydrogen peroxide. Moreover, synthetic lethalities of rho5 deletions with key components in nutrient sensing, such as sch9 and gpr1, are not conserved in K. lactis. Instead, Klrho5 deletion mutants display morphological defects with strengthened lateral cell walls and protruding bud scars. The latter result from aberrant cytokinesis, as observed by following the budding process in vivo and by transmission electron microscopy of the bud neck region. This phenotype can be suppressed by KlCDC42G12V, which encodes a hyper-active variant. Data from live-cell fluorescence microscopy support the notion that KlRho5 interferes with the actin moiety of the contractile actomyosin ring, with consequences different from those previously reported for mutants lacking myosin.

The role of a microbial consortium on gas exchange and water relations in Allium cepa L. under water and nutritional deficit conditions.

Synergistic studies of microorganisms in the last decade have been mostly directed towards their biofertilizing effects on growth and crop yield. Our research examines the role of a microbial consortium (MC) on physiological responses of Allium cepa hybrid F1 2000 under water and nutritional deficit in a semi-arid environment. An onion crop was established with normal irrigation (NIr) (100% ETc) and water deficit (WD) (67% ETc) and different fertilization treatments (MC with 0%, 50% and 100% NPK). Gas exchange (Stomatal conductance (Gs), transpiration (E) and CO2 assimilation rates (A)) and leaf water status were evaluated throughout its growth cycle. The MC + 50% NPK treatment with NIr maintained similar A rates to the production control. A. cepa decreased Gs by approximately 50% in the WD treatment. The highest water use efficiency (WUE) and an increase in the modulus of elasticity in response to water stress were obtained for the 100% NPK treatment under non-inoculated WD. The onion hybrid F1 2000 was tolerant to water stress and under non-limiting nutrient conditions, irrigation may be reduced. The MC facilitated the availability of nutrients under NIr allowing a 50% reduction in the application of high doses of fertilization without affecting yield, resulting in a suitable agroecological strategy for this crop.

Complementary omics strategies to dissect p53 signaling networks under nutrient stress.

Signaling trough p53is a major cellular stress response mechanism and increases upon nutrient stresses such as starvation. Here, we show in a human hepatoma cell line that starvation leads to robust nuclear p53 stabilization. Using BioID, we determine the cytoplasmic p53 interaction network within the immediate-early starvation response and show that p53 is dissociated from several metabolic enzymes and the kinase PAK2 for which direct binding with the p53 DNA-binding domain was confirmed with NMR studies. Furthermore, proteomics after p53 immunoprecipitation (RIME) uncovered the nuclear interactome under prolonged starvation, where we confirmed the novel p53 interactors SORBS1 (insulin receptor signaling) and UGP2 (glycogen synthesis). Finally, transcriptomics after p53 re-expression revealed a distinct starvation-specific transcriptome response and suggested previously unknown nutrient-dependent p53 target genes. Together, our complementary approaches delineate several nodes of the p53 signaling cascade upon starvation, shedding new light on the mechanisms of p53 as nutrient stress sensor. Given the central role of p53 in cancer biology and the beneficial effects of fasting in cancer treatment, the identified interaction partners and networks could pinpoint novel pharmacologic targets to fine-tune p53 activity.

Nutrient availability contributes to a graded refractory period for regeneration in Xenopus tropicalis.

Xenopus tadpoles are a unique model for regeneration in that they exhibit two distinct phases of age-specific regenerative competence. In Xenopus laevis, young tadpoles fully regenerate following major injuries such as tail transection, then transiently lose regenerative competence during the "refractory period" from stages 45-47. Regenerative competence is then regained in older tadpoles before being permanently lost during metamorphosis. Here we show that a similar refractory period exists in X. tropicalis. Notably, tadpoles lose regenerative competence gradually in X. tropicalis, with full regenerative competence lost at stage 47. We find that the refractory period coincides closely with depletion of maternal yolk stores and the onset of independent feeding, and so we hypothesized that it might be caused in part by nutrient stress. In support of this hypothesis, we find that cell proliferation declines throughout the tail as the refractory period approaches. When we block nutrient mobilization by inhibiting mTOR signaling, we find that tadpole growth and regeneration are reduced, while yolk stores persist. Finally, we are able to restore regenerative competence and cell proliferation during the refractory period by abundantly feeding tadpoles. Our study argues that nutrient stress contributes to lack of regenerative competence and introduces the X. tropicalis refractory period as a valuable new model for interrogating how metabolic constraints inform regeneration.

Global analysis of boron-induced ribosome stalling reveals its effects on translation termination and unique regulation by AUG-stops in Arabidopsis shoots.

We previously reported that ribosome stalling at AUG-stop sequences in the 5'-untranslated region plays a critical role in regulating the expression of Arabidopsis thaliana NIP5;1, which encodes a boron uptake transporter, in response to boron conditions in media. This ribosome stalling is triggered specifically by boric acid, but the mechanisms are unknown. Although upstream open reading frames (uORFs) are known in many cases to regulate translation through peptides encoded by the uORF, AUG-stop stalling does not involve any peptide synthesis. The unique feature of AUG-stops - that termination follows immediately after initiation - suggests a possible effect of boron on the translational process itself. However, the generality of AUG-stop-mediated translational regulation and the effect of boron on translation at the genome scale are not clear. Here, we conducted a ribosome profiling analysis to reveal the genome-wide regulation of translation in response to boron conditions in A. thaliana shoots. We identified hundreds of translationally regulated genes that function in various biological processes. Under high-boron conditions, transcripts with reduced translation efficiency were rich in uORFs, highlighting the importance of uORF-mediated translational regulation. We found 673 uORFs that had more frequent ribosome association. Moreover, transcripts that were translationally downregulated under high-boron conditions were rich in minimum uORFs (AUG-stops), suggesting that AUG-stops play a global role in the boron response. Metagene analysis revealed that boron increased the ribosome occupancy of stop codons, indicating that this element is involved in global translational termination processes.

A DasA family sugar binding protein Ste2 links nutrient and oxidative stress to exopolysaccharides production in Streptomyces sp. 139.

BACKGROUND: Ebosin is an exopolysaccharide produced by Streptomyces sp. 139, and its biosynthetic gene cluster (ste) has been previously described. Ste234 has high homology to the well-known ATP-binding cassette transport system DasABC, which has been linked to the regulation of morphological differentiation, antibiotics biosynthesis and aminosugars utilization in Streptomycetes. This study was conducted to evaluate the effect of the DasA family sugar binding protein Ste2 on Streptomyces sp. 139. RESULTS: The disruption of ste2 results in the upregulation of transcription of genes within Ebosin biosynthetic gene cluster and a two-fold increase in Ebosin production. RNA sequencing data suggests that the disruption of ste2 results in the decreased utilization of carbon and nitrogen sources, increased sensitivity to oxidative stress, as well as differed strain morphology, all of which have been experimentally proven. CONCLUSIONS: Taken together, Ste2 controls Ebosin yields, aminosugars uptake, sensitivity to oxidative stress, and morphological differentiation of Streptomyces sp. 139.

Influence of calcium and magnesium elimination on plant biomass and secondary metabolites of Stevia rebaudiana Bertoni.

This study reports the increment in the secondary metabolites in Stevia rebaudiana plant after exposure to the elimination of Ca and Mg from Murashige and Skoog culture medium. The effect of nutrient stress on regenerants of S. rebaudiana is measured, which reveals significantly enhanced growth parameters, steviol glycosides (SGs) content, and nonenzymatic antioxidants; total phenolic content, total flavonoid content, total antioxidant capacity, total reducing power, and DPPH-free radical scavenging activity as compared with the control treatment. However, significantly highest amounts are obtained in a medium with only Ca deficiency. The amount of rebaudioside A (Reb A) and stevioside (ST) obtained in the case of Ca-deficient medium is 4.08 and 0.69%, respectively. It is followed by the results obtained from both Ca- and Mg-deprived medium [Reb A (3.23%) and ST (0.52%)] and the lowest values are obtained from medium lacking Mg only [Reb A (2.60%) and ST (0.40%)]. The most probable adaptation mechanism might be the production of reactive oxygen species by nutrients' stress, which results in secondary metabolites production as defensive moieties to overcome stress situation. This effective protocol needs to be refined to apply on an industrial scale in bioreactors for increasing quantities of commercially important pharmaceutical compounds.