MAPK-Activated Protein Kinases: Servant or Partner?

Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these kinases. MAPKAPKs cooperate in the regulation of gene expression at the level of transcription; RNA processing, export, and stability; and protein synthesis. The diversity of stimuli for MAPK activation, the crosstalk between the different MAPKs and MAPKAPKs, and the specific substrate pattern of MAPKAPKs orchestrate immediate-early and inflammatory responses in space and time and ensure proper control of cell growth, differentiation, and cell behavior. Hence, MAPKAPKs are promising targets for cancer therapy and treatments for conditions of acute and chronic inflammation, such as cytokine storms and rheumatoid arthritis.

Stress signaling between organs in metazoa.

Many organisms have developed a robust ability to adapt and survive in the face of environmental perturbations that threaten the integrity of their genome, proteome, or metabolome. Studies in multiple model organisms have shown that, in general, when exposed to stress, cells activate a complex prosurvival signaling network that includes immune and DNA damage response genes, chaperones, antioxidant enzymes, structural proteins, metabolic enzymes, and noncoding RNAs. The manner of activation runs the gamut from transcriptional induction of genes to increased stability of transcripts to posttranslational modification of important biosynthetic proteins within the stressed tissue. Superimposed on these largely autonomous effects are nonautonomous responses in which the stressed tissue secretes peptides and other factors that stimulate tissues in different organs to embark on processes that ultimately help the organism as a whole cope with stress. This review focuses on the mechanisms by which tissues in one organ adapt to environmental challenges by regulating stress responses in tissues of different organs.

A Unique ISR Program Determines Cellular Responses to Chronic Stress.

The integrated stress response (ISR) is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. In acute/transient ER stress, decreased global protein synthesis and increased uORF mRNA translation are followed by normalization of protein synthesis. Here, we report a dramatically different response during chronic ER stress. This chronic ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. The program includes PERK-dependent switching to an eIF3-dependent translation initiation mechanism, resulting in partial, but not complete, translational recovery, which, together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of transcriptional and translational reprogramming prevents ER dysfunction and inhibits "foamy cell" development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction.

The role of microbial partners in heavy metal metabolism in plants: a review.

Heavy metal pollution threatens plant growth and development as well as ecological stability. Here, we synthesize current research on the interplay between plants and their microbial symbionts under heavy metal stress, highlighting the mechanisms employed by microbes to enhance plant tolerance and resilience. Several key strategies such as bioavailability alteration, chelation, detoxification, induced systemic tolerance, horizontal gene transfer, and methylation and demethylation, are examined, alongside the genetic and molecular basis governing these plant-microbe interactions. However, the complexity of plant-microbe interactions, coupled with our limited understanding of the associated mechanisms, presents challenges in their practical application. Thus, this review underscores the necessity of a more detailed understanding of how plants and microbes interact and the importance of using a combined approach from different scientific fields to maximize the benefits of these microbial processes. By advancing our knowledge of plant-microbe synergies in the metabolism of heavy metals, we can develop more effective bioremediation strategies to combat the contamination of soil by heavy metals.

RACK1 Regulates Poxvirus Protein Synthesis Independently of Its Role in Ribosome-Based Stress Signaling.

Receptor for activated C kinase 1 (RACK1) is a small ribosomal subunit protein that is phosphorylated by vaccinia virus (VacV) to maximize translation of postreplicative (PR) mRNAs that harbor 5' polyA leaders. However, RACK1 is a multifunctional protein that both controls translation directly and acts as a scaffold for signaling to and from the ribosome. This includes stress signaling that is activated by ribosome-associated quality control (RQC) and ribotoxic stress response (RSR) pathways. As VacV infection activates RQC and stress signaling, whether RACK1 influences viral protein synthesis through its effects on translation, signaling, or both remains unclear. Examining the effects of genetic knockout of RACK1 on the phosphorylation of key mitogenic and stress-related kinases, we reveal that loss of RACK1 specifically blunts the activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) at late stages of infection. However, RACK1 was not required for JNK recruitment to ribosomes, and unlike RACK1 knockout, JNK inhibitors had no effect on viral protein synthesis. Moreover, reduced JNK activity during infection in RACK1 knockout cells contrasted with the absolute requirement for RACK1 in RSR-induced JNK phosphorylation. Comparing the effects of RACK1 knockout alongside inhibitors of late stage replication, our data suggest that JNK activation is only indirectly affected by the absence of RACK1 due to reduced viral protein accumulation. Cumulatively, our findings in the context of infection add further support for a model whereby RACK1 plays a specific and direct role in controlling translation of PR viral mRNAs that is independent of its role in ribosome-based stress signaling. IMPORTANCE Receptor for activated C kinase 1 (RACK1) is a multifunctional ribosomal protein that regulates translation directly and mediates signaling to and from the ribosome. While recent work has shown that RACK1 is phosphorylated by vaccinia virus (VacV) to stimulate translation of postreplicative viral mRNAs, whether RACK1 also contributes to VacV replication through its roles in ribosome-based stress signaling remains unclear. Here, we characterize the role of RACK1 in infected cells. In doing so, we find that RACK1 is essential for stress signal activation by ribotoxic stress responses but not by VacV infection. Moreover, although the loss of RACK1 reduces the level of stress-associated JNK activation in infected cells, this is an indirect consequence of RACK1's specific requirement for the synthesis of postreplicative viral proteins, the accumulation of which determines the level of cellular stress. Our findings reveal both the specific role of RACK1 and the complex downstream effects of its control of viral protein synthesis in the context of infection.

A phosphatase-centric mechanism drives stress signaling response.

Changing environmental cues lead to the adjustment of cellular physiology by phosphorylation signaling networks that typically center around kinases as active effectors and phosphatases as antagonistic elements. Here, we report a signaling mechanism that reverses this principle. Using the hyperosmotic stress response in Saccharomyces cerevisiae as a model system, we find that a phosphatase-driven mechanism causes induction of phosphorylation. The key activating step that triggers this phospho-proteomic response is the Endosulfine-mediated inhibition of protein phosphatase 2A-Cdc55 (PP2ACdc55 ), while we do not observe concurrent kinase activation. In fact, many of the stress-induced phosphorylation sites appear to be direct substrates of the phosphatase, rendering PP2ACdc55 the main downstream effector of a signaling response that operates in parallel and independent of the well-established kinase-centric stress signaling pathways. This response affects multiple cellular processes and is required for stress survival. Our results demonstrate how a phosphatase can assume the role of active downstream effectors during signaling and allow re-evaluating the impact of phosphatases on shaping the phosphorylome.

Thermosensitivity of pollen: a molecular perspective.

A current trend in climate comprises adverse weather anomalies with more frequent and intense temperature events. Heatwaves are a serious threat to global food security because of the susceptibility of crop plants to high temperatures. Among various developmental stages of plants, even a slight rise in temperature during reproductive development proves detrimental, thus making sexual reproduction heat vulnerable. In this context, male gametophyte or pollen development stages are the most sensitive ones. High-temperature exposure induces pollen abortion, reducing pollen viability and germination rate with a concomitant effect on seed yield. This review summarizes the ultrastructural, morphological, biochemical, and molecular changes underpinning high temperature-induced aberrations in male gametophytes. Specifically, we highlight the temperature sensing cascade operating in pollen, involving reactive oxygen species (ROS), heat shock factors (HSFs), a hormones and transcriptional regulatory network. We also emphasize integrating various omics approaches to decipher the molecular events triggered by heat stress in pollen. The knowledge of genes, proteins, and metabolites conferring thermotolerance in reproductive tissues can be utilized to breed/engineer thermotolerant crops to ensure food security.

FOXO transcription factors in antioxidant defense.

Forkhead box, class O (FOXO) family proteins are widely expressed and highly conserved transcriptional regulators that modulate cellular fuel metabolism, stress resistance and cell death. FOXO target genes include genes encoding antioxidant proteins, thus likely contributing to the key role FOXOs play in the cellular response to oxidative stress and supporting the cellular strategies of antioxidant defense, that is, prevention (of the formation of reactive oxygen species), interception (of reactive species prior to their reaction with cellular components), repair (of damaged biomolecules), and adaptation (i.e., the stimulation of signaling pathways allowing for the expression of protective proteins). FOXOs themselves are regulated by redox processes at several levels, including expression of FOXO genes and enzymatic as well as nonenzymatic posttranslational modifications of FOXO proteins. The latter include modifications of FOXO cysteine residues. Here, an overview is provided on (i) the contribution of FOXO target genes to cellular antioxidative strategies, and (ii) on the impact of thiol homeostasis and thiol modification on FOXO activity.

Organelles and phytohormones: a network of interactions in plant stress responses.

Phytohormones are major signaling components that contribute to nearly all aspects of plant life. They constitute an interconnected communication network to fine-tune growth and development in response to the ever-changing environment. To this end, they have to coordinate with other signaling components, such as reactive oxygen species and calcium signals. On the one hand, the two endosymbiotic organelles, plastids and mitochondria, control various aspects of phytohormone signaling and harbor important steps of hormone precursor biosynthesis. On the other hand, phytohormones have feedback actions on organellar functions. In addition, organelles and phytohormones often act in parallel in a coordinated matter to regulate cellular functions. Therefore, linking organelle functions with increasing knowledge of phytohormone biosynthesis, perception, and signaling will reveal new aspects of plant stress tolerance. In this review, we highlight recent work on organelle-phytohormone interactions focusing on the major stress-related hormones abscisic acid, jasmonates, salicylic acid, and ethylene.

Imbalanced GSH/ROS and sequential cell death.

Reactive oxygen species (ROS) are produced in cells during metabolic processes. Excessive intracellular ROS may react with large biomolecules, such as DNA, RNA, proteins, and small biomolecules, that is, glutathione (GSH) and unsaturated fatty acids. GSH has physiological functions, including free radical scavenging, anti-oxidation, and electrophile elimination. The disruption of ROS/GSH balance results in the deleterious oxidation and chemical modification of biomacromolecules, which eventually leads to cell-cycle arrest and proliferation inhibition, and even induces cell death. Imbalanced ROS/GSH may result from a direct increase of ROS, consumption of GSH, intracellular oxidoreductase interference, or thioredoxin activity reduction. Some chemicals including arsenic trioxide (ATO), pyrogallol (PG), and carbobenzoxy-Leu-Leu-leucinal (MG132) could also disrupt the balance of GSH and ROS. This article reviews the occurrence and consequences of the imbalance between GSH and ROS and introduces factors responsible for the disruption of cellular ROS and GSH balance, resulting in cell death. "GSH" and "ROS" were used as keywords to search the relevant literaturess.

CMLS forum reviews: mitochondrial damage control.

Mitochondria supply cellular energy through oxidative phosphorylation and fulfill numerous additional functions that are fundamental to cellular homeostasis and stress responses. Mitochondrial malfunction, arising from inherent defects of the organelle itself, aging, or acute or chronic stress, can cause substantial damage to organismal health. For instance, mitochondrial malfunction contributes to inflammation, neurodegeneration, tumorigenesis and cardiovascular diseases. Therefore, various quality control mechanisms exist that support a functional mitochondrial organelle compartment. The CMLS Forum Reviews introduced here present a collection of articles covering select topics on basic mechanisms and pathophysiological contexts of mitochondrial damage control.

A theory of mechanical stress-induced H2O2 signaling waveforms in Planta.

Recent progress in nanotechnology-enabled sensors that can be placed inside of living plants has shown that it is possible to relay and record real-time chemical signaling stimulated by various abiotic and biotic stresses. The mathematical form of the resulting local reactive oxygen species (ROS) wave released upon mechanical perturbation of plant leaves appears to be conserved across a large number of species, and produces a distinct waveform from other stresses including light, heat and pathogen-associated molecular pattern (PAMP)-induced stresses. Herein, we develop a quantitative theory of the local ROS signaling waveform resulting from mechanical stress in planta. We show that nonlinear, autocatalytic production and Fickian diffusion of H2O2 followed by first order decay well describes the spatial and temporal properties of the waveform. The reaction-diffusion system is analyzed in terms of a new approximate solution that we introduce for such problems based on a single term logistic function ansatz. The theory is able to describe experimental ROS waveforms and degradation dynamics such that species-dependent dimensionless wave velocities are revealed, corresponding to subtle changes in higher moments of the waveform through an apparently conserved signaling mechanism overall. This theory has utility in potentially decoding other stress signaling waveforms for light, heat and PAMP-induced stresses that are similarly under investigation. The approximate solution may also find use in applied agricultural sensing, facilitating the connection between measured waveform and plant physiology.

Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling.

Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of molecular chaperones. The HSR and other cell stress responses such as the unfolded protein response (UPR) can function autonomously in single-cell eukaryotes and tissue culture cells; however, within the context of a multicellular animal, the PN is regulated by cell-nonautonomous signaling through specific sensory neurons and by the process of transcellular chaperone signaling. These newly identified forms of stress signaling control the PN between neurons and nonneuronal somatic tissues to achieve balanced tissue expression of chaperones in response to environmental stress and to ensure that metastable aggregation-prone proteins expressed within any single tissue do not generate local proteotoxic risk. Transcellular chaperone signaling leads to the compensatory expression of chaperones in other somatic tissues of the animal, perhaps preventing the spread of proteotoxic damage. Thus, communication between subcellular compartments and across different cells and tissues maintains proteostasis when challenged by acute stress and upon chronic expression of metastable proteins. We propose that transcellular chaperone signaling provides a critical control step for the PN to maintain cellular and organismal health span.

Structural and Functional Studies of S-(2-Carboxyethyl)-L-Cysteine and S-(2-Carboxyethyl)-l-Cysteine Sulfoxide.

Insecticidal non-proteinogenic amino acid S-(2-carboxyethyl)-L-cysteine (ß-CEC) and its assumed metabolite, S-(2-carboxyethyl)-l-cysteine sulfoxide (ß-CECO), are present abundantly in a number of plants of the legume family. In humans, these amino acids may occur as a result of exposure to environmental acrylonitrile or acrylamide, and due to consumption of the legumes. The ß-CEC molecule is a homolog of S-carboxymethyl-l-cysteine (carbocisteine, CMC), a clinically employed antioxidant and mucolytic drug. We report here detailed structural data for ß-CEC and ß-CECO, as well as results of in vitro studies evaluating cytotoxicity and the protective potential of the amino acids in renal tubular epithelial cells (RTECs) equipped with reporters for activity of seven stress-responsive transcription factors. In RTECs, ß-CEC and the sulfoxide were not acutely cytotoxic, but activated the antioxidant Nrf2 pathway. ß-CEC, but not the sulfoxide, induced the amino acid stress signaling, which could be moderated by cysteine, methionine, histidine, and tryptophan. ß-CEC enhanced the cytotoxic effects of arsenic, cadmium, lead, and mercury, but inhibited the cytotoxic stress induced by cisplatin, oxaliplatin, and CuO nanoparticles and acted as an antioxidant in a copper-dependent oxidative DNA degradation assay. In these experiments, the structure and activities of ß-CEC closely resembled those of CMC. Our data suggest that ß-CEC may act as a mild activator of the cytoprotective pathways and as a protector from platinum drugs and environmental copper cytotoxicity.

Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells.

Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980 Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex vivo model of angiogenesis. Exposure of the aortic rings embedded in 3D fibrillar collagen to recombinant endorepellin for 2-4 h activated PERK and induced GADD45α vis à vis vehicle-treated counterparts. Similar effects were obtained with the established cellular stress inducer tunicamycin. Notably, chronic exposure of aortic rings to endorepellin for 7-9 days markedly suppressed vessel sprouting, an angiostatic effect that was rescued by blocking PERK kinase activity. Our findings unravel a mechanism by which an extracellular matrix protein evokes stress signaling in endothelial cells, which leads to angiostasis.

Loss of function of Arabidopsis NADP-malic enzyme 1 results in enhanced tolerance to aluminum stress.

In acidic soils, aluminum (Al) toxicity is a significant limitation to crop production worldwide. Given its Al-binding capacity, malate allows internal as well as external detoxification strategies to cope with Al stress, but little is known about the metabolic processes involved in this response. Here, we analyzed the relevance of NADP-dependent malic enzyme (NADP-ME), which catalyzes the oxidative decarboxylation of malate, in Al tolerance. Plants lacking NADP-ME1 (nadp-me1) display reduced inhibition of root elongation along Al treatment compared with the wild type (wt). Moreover, wt roots exposed to Al show a drastic decrease in NADP-ME1 transcript levels. Although malate levels in seedlings and root exudates are similar in nadp-me1 and wt, a significant increase in intracellular malate is observed in roots of nadp-me1 after long exposure to Al. The nadp-me1 plants also show a lower H2 O2 content in root apices treated with Al and no inhibition of root elongation when exposed to glutamate, an amino acid implicated in Al signaling. Proteomic studies showed several differentially expressed proteins involved in signal transduction, primary metabolism and protection against biotic and other abiotic stimuli and redox processes in nadp-me1, which may participate directly or indirectly in Al tolerance. The results indicate that NADP-ME1 is involved in adjusting the malate levels in the root apex, and its loss results in an increased content of this organic acid. Furthermore, the results suggest that NADP-ME1 affects signaling processes, such as the generation of reactive oxygen species and those that involve glutamate, which could lead to inhibition of root growth.

Integrative transcriptomic and metabolomic analyses provide insight into the long-term submergence response mechanisms of young Salix variegata stems.

MAIN CONCLUSION: The mechanisms underlying long-term complete submergence tolerance in S. variegata involve enhanced oxidative stress responses, strengthened ethylene and ABA signaling, synthesis of raffinose family oligosaccharides, unsaturated fatty acids, and specific stress-related amino acids. Salix variegata Franch. is a riparian shrub species that can tolerate long-term complete submergence; however, the molecular mechanisms underlying this trait remain to be elucidated. In this study, we subjected S. variegata plants to complete submergence for 60 d and collected stems to perform transcriptomic and metabolomic analyses, as well as quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays. Results revealed that photosynthesis and the response to light stimulus were inhibited during submergence and recovered after desubmergence. Ethylene and abscisic acid (ABA) signaling could be important for the long-term submergence tolerance of S. variegata. Jasmonic acid (JA) signaling also participated in the response to submergence. Raffinose family oligosaccharides, highly unsaturated fatty acids, and specific stress-related amino acids accumulated in response to submergence, indicating that they may protect plants from submergence damage, as they do in response to other abiotic stressors. Several organic acids were produced in S. variegata plants after submergence, which may facilitate coping with the toxicity induced by submergence. After long-term submergence, cell wall reorganization and phenylpropanoid metabolic processes (the synthesis of specific phenolics and flavonoids) were activated, which may contribute to long-term S. variegata submergence tolerance; however, the detailed mechanisms require further investigation. Several transcription factors (TFs), such as MYB, continuously responded to submergence, indicating that they may play important roles in the responses and adaption to submergence. Genes related to oxidative stress tolerance were specifically expressed after desubmergence, potentially contributing to recovery of S. variegata plants within a short period of time.

5-aminolevulinic acid-mediated plant adaptive responses to abiotic stress.

KEY MESSAGE: 5-aminolevulinic acid (ALA) modulates various defense systems in plants and confers abiotic stress tolerance. Enhancement of crop production is a challenge due to numerous abiotic stresses such as, salinity, drought, temperature, heavy metals, and UV. Plants often face one or more abiotic stresses in their life cycle because of the challenging growing environment which results in reduction of growth and yield. Diverse studies have been conducted to discern suitable mitigation strategies to enhance crop production by minimizing abiotic stress. Exogenous application of different plant growth regulators is a well-renowned approach to ameliorate adverse effects of abiotic stresses on crop plants. Among the numerous plant growth regulators, 5-aminolevulinic acid (ALA) is a novel plant growth regulator, also well-known to alleviate the injurious effects of abiotic stresses in plants. ALA enhances abiotic stress tolerance as well as growth and yield by regulating photosynthetic and antioxidant machineries and nutrient uptake in plants. However, the regulatory roles of ALA in plants under different stresses have not been studied and assembled systematically. Also, ALA-mediated abiotic stress tolerance mechanisms have not been fully elucidated yet. Therefore, this review discusses the role of ALA in crop growth enhancement as well as its ameliorative role in abiotic stress mitigation and also discusses the ALA-mediated abiotic stress tolerance mechanisms and its limitation and future promises for sustainable crop production.

Jasmonic acid: a key frontier in conferring abiotic stress tolerance in plants.

Abiotic stresses are the primary sources of crop losses globally. The identification of key mechanisms deployed and established by plants in response to abiotic stresses is necessary for the maintenance of their growth and persistence. Recent discoveries have revealed that phytohormones or plant growth regulators (PGRs), mainly jasmonic acid (JA), have increased our knowledge of hormonal signaling of plants under stressful environments. Jasmonic acid is involved in various physiological and biochemical processes associated with plant growth and development as well as plant defense mechanism against wounding by pathogen and insect attacks. Recent findings suggest that JA can mediate the effect of abiotic stresses and help plants to acclimatize under unfavorable conditions. As a vital PGR, JA contributes in many signal transduction pathways, i.e., gene network, regulatory protein, signaling intermediates and enzymes, proteins, and other molecules that act to defend cells from the harmful effects of various environmental stresses. However, JA does not work as an independent regulator, but acts in a complex signaling pathway along other PGRs. Further, JA can protect and maintain the integrity of plant cells under several stresses by up-regulating the antioxidant defense. In this review, we have documented the biosynthesis and metabolism of JA and its protective role against different abiotic stresses. Further, JA-mediated antioxidant potential and its crosstalk with other PGRs have also been discussed.

Coordination of Timers and Sensors in Cell Signaling.

Timers and sensors are common devices that make our daily life safer, more convenient, and more efficient. In a cellular context, they arguably play an even more crucial role as they ensure the survival of cells in the presence of various extrinsic and intrinsic stresses. Biological timers and sensors generate distinct signaling profiles, enabling them to produce different types of cellular responses. Recent data suggest that they can work together to guarantee correct timing and responsiveness. By exploring examples of cellular stress signaling from mitosis, DNA damage, and hypoxia, the authors discuss the common architecture of timer-sensor integration, and how its added features contribute to the generation of desired signaling profiles when dealing with stresses of variable duration and strength. The authors propose timer-sensor integration as a widespread mechanism with profound biological implications and therapeutic potential.