ABSTRACT
Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesizes nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme-mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.
Subject(s)
Acetyl Coenzyme A , Arabidopsis Proteins , Arabidopsis , Cell Nucleus , Ethylenes , Gene Expression Regulation, Plant , Histones , Pyruvate Dehydrogenase Complex , Acetylation , Ethylenes/metabolism , Pyruvate Dehydrogenase Complex/metabolism , Pyruvate Dehydrogenase Complex/genetics , Histones/metabolism , Arabidopsis/genetics , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Cell Nucleus/metabolism , Acetyl Coenzyme A/metabolism , Transcription, Genetic , Mutation , Signal Transduction , Receptors, Cell SurfaceABSTRACT
Active polymers possess numerous unique properties that are quite different from those observed in the system of small active molecules due to the intricate interplay between their activity and topological constraints. This study focuses on the conformational changes induced by activity, impacting effective stiffness and crucially influencing entanglement and dynamics. When the two terminals of a linear chain undergo active modification through coupling to a high-temperature thermal bath, there is a substantial increase in chain size, indicating a notable enhancement in effective stiffness. Unlike in passive semiflexible chains where stiffness predominantly affects local bond angles, activity-induced stiffness manifests at the scale of tens of monomers. While activity raises the ambient temperature, it significantly decreases diffusion by over an order of magnitude. The slowdown of the dynamics observed can be attributed to increased entanglement due to chain elongation.
ABSTRACT
Nontraumatic avascular necrosis of the femoral head(NANFH) is a common and refractory femoral head disease that causes bone death due to interruption of blood supply. Early clinical symptoms are atypical, such as hip pain and limited joint function. In the late stage, severe pain, shortening of the affected limb, claudication, and other serious symptoms are common, which se-riously affects the quality of life of patients. Therefore, it is of great significance to actively improve the clinical symptoms of NANFH to enhance the quality of life of patients. The pathogenesis of NANFH is complex, such as traumatic vascular circulatory disorders, the use of hormones or other drugs, alcoholism, and diabetes mellitus. These factors directly or indirectly lead to femoral head vascular damage, thrombosis, and coagulation system disorders, which reduce the blood supply to the acetabulum and femoral head, thus causing ischaemic death of the femoral head or even femoral head collapse. NANFH is mainly categorized as "bone impotence" and "bone paralysis" in traditional Chinese medicine(TCM). The treatment of NANFH with TCM has the characteristics and advantages of a long history, stable and reliable therapeutic effect, fewer adverse reactions, good patient tolerance, and high acceptance. Previous studies have shown that the promotion of angiogenesis is a key initiative in the prevention and treatment of NANFH, and TCM can promote fe-moral head angiogenesis by interfering with the expression of angiogenesis-related factors, which in turn can help to restore the blood supply of the femoral head and thus improve clinical symptoms of NANFH and prevent and treat NANFH. This article described the roles of blood supply interruption and angiogenesis in NANFH and the accumulated knowledge and experience of TCM in NANFH and summarized the role of angiogenesis-related factors in NANFH and the research progress on TCM intervention, so as to provide an idea for the subsequent research and a new basis for the clinical application of TCM in the treatment of NANFH.
Subject(s)
Drugs, Chinese Herbal , Femur Head Necrosis , Humans , Femur Head Necrosis/prevention & control , Femur Head Necrosis/drug therapy , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/administration & dosage , Medicine, Chinese Traditional , Animals , Femur Head/blood supply , Neovascularization, Pathologic/drug therapy , Neovascularization, Physiologic/drug effects , AngiogenesisABSTRACT
Photomorphogenesis is a light-dependent plant growth and development program. As the core regulator of photomorphogenesis, ELONGATED HYPOCOTYL 5 (HY5) is affected by dynamic changes in its transcriptional activity and protein stability; however, little is known about the mediators of these processes. Here, we identified PHOTOREGULATORY PROTEIN KINASE 1 (PPK1), which interacts with and phosphorylates HY5 in Arabidopsis, as one such mediator. The phosphorylation of HY5 by PPK1 is essential to establish high-affinity binding with B-BOX PROTEIN 24 (BBX24) and CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), which inhibit the transcriptional activity and promote the degradation of HY5, respectively. As such, PPKs regulate not only the binding of HY5 to its target genes under light conditions but also HY5 degradation when plants are transferred from light to dark. Our data identify a PPK-mediated phospho-code on HY5 that integrates the molecular mechanisms underlying the regulation of HY5 to precisely control plant photomorphogenesis.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Basic-Leucine Zipper Transcription Factors , Gene Expression Regulation, Plant , Light , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Arabidopsis/metabolism , Arabidopsis/growth & development , Arabidopsis/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Phosphorylation , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Morphogenesis/radiation effects , Protein Kinases/metabolism , Protein Kinases/genetics , Repressor ProteinsABSTRACT
Plants often adapt to adverse or stress conditions via differential growth. The trans-Golgi network (TGN) has been implicated in stress responses, but it is not clear in what capacity it mediates adaptive growth decisions. In this study, we assess the role of the TGN in stress responses by exploring the previously identified interactome of the Transport Protein Particle II (TRAPPII) complex required for TGN structure and function. We identified physical and genetic interactions between AtTRAPPII and shaggy-like kinases (GSK3/AtSKs) and provided in vitro and in vivo evidence that the TRAPPII phosphostatus mediates adaptive responses to abiotic cues. AtSKs are multifunctional kinases that integrate a broad range of signals. Similarly, the AtTRAPPII interactome is vast and considerably enriched in signaling components. An AtSK-TRAPPII interaction would integrate all levels of cellular organization and instruct the TGN, a central and highly discriminate cellular hub, as to how to mobilize and allocate resources to optimize growth and survival under limiting or adverse conditions.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Carrier Proteins , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Glycogen Synthase Kinase 3/metabolism , Phosphorylation , Protein Transport , trans-Golgi Network/metabolism , Carrier Proteins/metabolismABSTRACT
BACKGROUND: Whole genome variants offer sufficient information for genetic prediction of human disease risk, and prediction of animal and plant breeding values. Many sophisticated statistical methods have been developed for enhancing the predictive ability. However, each method has its own advantages and disadvantages, so far, no one method can beat others. RESULTS: We herein propose an Ensemble Learning method for Prediction of Genetic Values (ELPGV), which assembles predictions from several basic methods such as GBLUP, BayesA, BayesB and BayesCπ, to produce more accurate predictions. We validated ELPGV with a variety of well-known datasets and a serious of simulated datasets. All revealed that ELPGV was able to significantly enhance the predictive ability than any basic methods, for instance, the comparison p-value of ELPGV over basic methods were varied from 4.853E-118 to 9.640E-20 for WTCCC dataset. CONCLUSIONS: ELPGV is able to integrate the merit of each method together to produce significantly higher predictive ability than any basic methods and it is simple to implement, fast to run, without using genotype data. is promising for wide application in genetic predictions.
Subject(s)
Genome , Plant Breeding , Animals , Humans , Genotype , Genomics , Machine Learning , Models, Genetic , Phenotype , Polymorphism, Single Nucleotide , Bayes TheoremABSTRACT
Exacerbation of pain by chronic stress and comorbidity of pain with stress-related disorders such as depression and post-traumatic stress disorder, represent significant clinical challenges. Previously we have documented that chronic forced swim (FS) stress exacerbates neuropathic pain in spared nerve injury (SNI) rats, associated with an up-regulation of GluN2B-containing N-methyl-D-aspartate receptors (GluN2B-NMDARs) in the central nucleus of the amygdala (CeA). However, the molecular mechanisms underlying chronic FS stress (CFSS)-mediated exacerbation of pain sensitivity in SNI rats still remain unclear. In this study, we demonstrated that exposure of CFSS to rats activated the corticotropin-releasing factor (CRF)/CRF receptor type 1 (CRFR1) signaling in the CeA, which was shown to be necessary for CFSS-induced depressive-like symptoms in stressed rats, and as well, for CFSS-induced exacerbation of pain hypersensitivity in SNI rats exposed to chronic FS stress. Furthermore, we discovered that activation of CRF/CRFR1 signaling in the CeA upregulated the phosphorylation of GluN2B-NMDARs at tyrosine 1472 (pGluN2BY1472) in the synaptosomal fraction of CeA, which is highly correlated to the enhancement of synaptic GluN2B-NMDARs expression that has been observed in the CeA in CFSS-treated SNI rats. In addition, we revealed that activation of CRF/CRFR1 signaling in the CeA facilitated the CFSS-induced reinforcement of long-term potentiation as well as the enhancement of NMDAR-mediated excitatory postsynaptic currents in the basolateral amygdala (BLA)-CeA pathway in SNI rats. These findings suggest that activation of CRF/CRFR1 signaling in the CeA contributes to chronic stress-induced exacerbation of neuropathic pain by enhancing GluN2B-NMDAR-mediated synaptic plasticity in rats subjected to nerve injury. PERSPECTIVE: Our present study provides a novel mechanism for elucidating stress-induced hyperalgesia and highlights that the CRF/CRFR1 signaling and the GluN2B-NMDAR-mediated synaptic plasticity in the CeA may be important as potential therapeutic targets for chronic stress-induced pain exacerbation in human neuropathic pain. DATA AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Subject(s)
Central Amygdaloid Nucleus , Corticotropin-Releasing Hormone , Neuralgia , Neuronal Plasticity , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone , Receptors, N-Methyl-D-Aspartate , Signal Transduction , Stress, Psychological , Animals , Receptors, N-Methyl-D-Aspartate/metabolism , Male , Neuralgia/metabolism , Neuralgia/physiopathology , Central Amygdaloid Nucleus/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Stress, Psychological/metabolism , Stress, Psychological/physiopathology , Stress, Psychological/complications , Corticotropin-Releasing Hormone/metabolism , Neuronal Plasticity/physiology , Rats , Signal Transduction/physiology , Disease Models, AnimalABSTRACT
Brassinosteroid (BR) signaling leads to the nuclear accumulation of the BRASSINAZOLE-RESISTANT 1 (BZR1) transcription factor, which plays dual roles in activating or repressing the expression of thousands of genes. BZR1 represses gene expression by recruiting histone deacetylases, but how it activates transcription of BR-induced genes remains unclear. Here, we show that BR reshapes the genome-wide chromatin accessibility landscape, increasing the accessibility of BR-induced genes and reducing the accessibility of BR-repressed genes in Arabidopsis. BZR1 physically interacts with the BRAHMA-associated SWI/SNF (BAS)-chromatin-remodeling complex on the genome and selectively recruits the BAS complex to BR-activated genes. Depletion of BAS abrogates the capacities of BZR1 to increase chromatin accessibility, activate gene expression, and promote cell elongation without affecting BZR1's ability to reduce chromatin accessibility and expression of BR-repressed genes. Together, these data identify that BZR1 recruits the BAS complex to open chromatin and to mediate BR-induced transcriptional activation of growth-promoting genes.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Brassinosteroids/metabolism , Chromatin/genetics , Chromatin/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Transcriptional Activation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Gene Expression Regulation, PlantABSTRACT
The development of universal anode materials with superlative electrochemical performance poses a great challenge for rechargeable alkali metal (AM) ion battery technologies. In the present work, the viability of the gapless Dirac t-BN (tetragonal boron nitride) monolayer as a lightweight binder-free anode has been systematically evaluated via comprehensive first-principles calculations. Aside from the desirable electronic conductivity, the t-BN monolayer exhibits an excellent ionic conductivity as well due to its moderate affinity for Li, Na, and K atoms with favorable in-plane barriers of 0.36, 0.18, and 0.19 eV, respectively. Meanwhile, the presence of B4N4 octagons allows the AM atoms to penetrate through the t-BN monolayer. Excitingly, the host material delivers an ultrahigh specific capacity up to 1080 mA h g-1 for Li, 5400 mA h g-1 for Na, and 2160 mA h g-1 for K in the wake of low mean open-circuit voltages of 0.033, 0.203, and 0.300 V at the half-cell level. According to the standard hydrogen electrode methodology, the energy densities are forecasted to be as large as 3240, 13500, and 5680 mW h g-1 for Li, Na, and K ion batteries, respectively, with robust thermal stability up to at least 400 K. The safety and cycling durability of the t-BN monolayer are jointly corroborated via the moderate mechanical strengths and ab initio molecular dynamics simulations at the maximum intercalated states, as well as via the small lattice changes and its ultrahigh tolerable ultimate tensile strain. These findings unambiguously promise that the t-BN monolayer can serve as an appealing candidate for anode applications in AM ion batteries.
ABSTRACT
BACKGROUND: Chronic liver disease has been reported to be associated with peripheral neuropathy. However, which sensory fibers are affected remains unknown. The objective of this study was to examine the function of sensory nerve fibers in patients with cirrhosis using the current perception threshold (CPT) test, as well as the correlation between blood biochemical indicators related to cirrhosis and CPT values. METHODS: We recruited 44 patients with liver cirrhosis and 37 healthy controls of the same age and gender. The Neurometer® system for the CPT test was used to stimulate the median nerve on the right index finger, as well as the deep and superficial peroneal nerves on the right hallux, using three distinct parameters (2000 Hz, 250 Hz, and 5 Hz). Comparative analysis was performed on the CPT values of the sensory nerves. Additionally, the correlation between CPT values and biochemical blood indicators in the study participants was analyzed. RESULTS: Under 2000 Hz electrical stimulation, there was a significant difference between the cirrhosis and healthy control groups in the median nerve as well as the deep and superficial peroneal nerves (p < 0.05). In addition, the median nerve CPT value of the cirrhosis group was significantly higher than that of the control group at an electrical stimulation frequency of 250 Hz (p = 0.005). There was no correlation between CPT values and blood biochemical indicators. CONCLUSION: According to the results, the sensory peripheral neuropathy in liver cirrhosis is mainly manifested as Aß fiber neuropathy.
Subject(s)
Liver Cirrhosis , Humans , Female , Male , Middle Aged , Liver Cirrhosis/complications , Liver Cirrhosis/physiopathology , Liver Cirrhosis/blood , Adult , Electric Stimulation , Aged , Median Nerve/physiopathology , Sensory Receptor Cells/physiology , Sensory Thresholds/physiology , Peroneal Nerve/physiopathology , Peripheral Nervous System Diseases/physiopathology , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/blood , Nerve Fibers/pathology , Nerve Fibers/physiologyABSTRACT
Polymer chains immersed in different solvent molecules exhibit diverse properties due to multiple spatiotemporal scales and complex interactions. Using molecular dynamics simulations, we study the conformational and static properties of tagged chains in different solvent molecules. Two types of solvent molecules were examined: one type consisted of chain molecules connected by bonds, while the other type consisted of individual bead molecules without any bonds. The only difference between the two solvent molecules lies in the chain connectivity. Our results show a compression of the tagged chains with the addition of bead or chain molecules. Chain molecule confinement induces a stronger compression compared to bead molecule confinement. In chain solvent molecules, the tagged chain's radius of gyration reached a minimum at a monomer volume fraction of â¼0.3. Notably, the probability distributions of chain size remain unchanged at different solvent densities, irrespective of whether the solvent consists of beads or polymers. Furthermore, as solvent density increases, a crossover from a unimodal to a bimodal distribution of bond angles is observed, indicating the presence of both compressed and expanded regions within the chain. The effective monomer-solvent interaction is obtained by calculating the partial radial distribution function and the potential of the mean force. In chain solvents, the correlation hole effect results in a reduced number of nearest neighbors around tagged monomers compared to bead solvents. The calculation of pore size distribution reveals that the solvent nonhomogeneity induced by chain connectivity leads to a broader distribution of pore sizes and larger pore dimensions at low volume fractions. These findings provide a deeper understanding of the conformational behavior of polymer chains in different solvent environments.
ABSTRACT
Salinity poses a significant threat to plant growth and development. The root microbiota plays a key role in plant adaptation to saline environments. Nevertheless, it remains poorly understood whether and how perennial grass plants accumulate specific root-derived bacteria when exposed to salinity. Here, we systematically analyzed the composition and variation of rhizosphere and endophytic bacteria, as well as root exudates in perennial ryegrass differing in salt tolerance grown in unsterilized soils with and without salt. Both salt-sensitive (P1) and salt-tolerant (P2) perennial ryegrass genotypes grew better in unsterilized soils compared to sterilized soils under salt stress. The rhizosphere and endophytic bacteria of both P1 and P2 had lower alpha-diversity under salt treatment compared to control. The reduction of alpha-diversity was more pronounced for P1 than for P2. The specific root-derived bacteria, particularly the genus Pseudomonas, were enriched in rhizosphere and endophytic bacteria under salt stress. Changes in bacterial functionality induced by salt stress differed in P1 and P2. Additionally, more root exudates were altered under salt stress in P2 than in P1. The content of important root exudates, mainly including phenylpropanoids, benzenoids, organic acids, had a significantly positive correlation with the abundance of rhizosphere and endophytic bacteria under salt stress. The results indicate that the interactions between root-derived bacteria and root exudates are crucial for the salt tolerance of perennial ryegrass, which provides a potential strategy to manipulate root microbiome for improved stress tolerance of perennial grass species.
Subject(s)
Lolium , Salt Tolerance , Poaceae , Bacteria , Soil , Exudates and Transudates , Rhizosphere , Plant Roots/microbiology , Soil MicrobiologyABSTRACT
Protein O-glycosylation is a nutrient signaling mechanism that plays an essential role in maintaining cellular homeostasis across different species. In plants, SPINDLY (SPY) and SECRET AGENT (SEC) posttranslationally modify hundreds of intracellular proteins with O-fucose and O-linked N-acetylglucosamine, respectively. SPY and SEC play overlapping roles in cellular regulation, and loss of both SPY and SEC causes embryo lethality in Arabidopsis (Arabidopsis thaliana). Using structure-based virtual screening of chemical libraries followed by in vitro and in planta assays, we identified a SPY O-fucosyltransferase inhibitor (SOFTI). Computational analyses predicted that SOFTI binds to the GDP-fucose-binding pocket of SPY and competitively inhibits GDP-fucose binding. In vitro assays confirmed that SOFTI interacts with SPY and inhibits its O-fucosyltransferase activity. Docking analysis identified additional SOFTI analogs that showed stronger inhibitory activities. SOFTI treatment of Arabidopsis seedlings decreased protein O-fucosylation and elicited phenotypes similar to the spy mutants, including early seed germination, increased root hair density, and defective sugar-dependent growth. In contrast, SOFTI did not visibly affect the spy mutant. Similarly, SOFTI inhibited the sugar-dependent growth of tomato (Solanum lycopersicum) seedlings. These results demonstrate that SOFTI is a specific SPY O-fucosyltransferase inhibitor that can be used as a chemical tool for functional studies of O-fucosylation and potentially for agricultural management.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Repressor Proteins/metabolism , Fucosyltransferases/genetics , Fucosyltransferases/metabolism , Fucose/metabolism , Seedlings/metabolism , Sugars/metabolismABSTRACT
Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key-step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene-hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesize nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.
ABSTRACT
Background: Colorectal cancer (CRC) is the fifth most fatal cancer with a low probability of surgery and limited treatment options, especially in metastatic CRC. In this study, we investigated whether a mouse model of metastatic CRC mimicked tumor progression and evaluated the effect of 5-fluorouracil (5-FU) treatment. Methods: The CT26 mouse derived CRC cancer cell line was inoculated into mice, and the tumor bearing mice were divided into two groups: the experimental group and the control group. Micro-computed tomography (CT) and in vivo fluorescence were used to monitor the progression of metastatic CRC. A lung metastasis mouse model was employed to determine the effects of 5-FU on metastasis. Results: Bioluminescence imaging (BLI) and computed tomography (CT), as non-invasive methods, can continuously monitor the growth of tumors in vivo. Thus, imaging techniques can be used to qualitatively and quantitatively evaluate tumor growth indicators. 5-FU injected intravenously reduced the viability of metastatic CRC cells and resulted in prolonged survival compared to the control group. Moreover, the 5-FU-treated group had significantly reduced fluorescence of the CT26 cells in the lung. The results observed by BLI and CT are consistent with the tissue morphology and structure presented in pathological examination. Conclusions: In summary, a successful mouse model of CRC metastasis for clinical application has been established.
ABSTRACT
Objective: The aim of this study is to explore the therapeutic effects of transcranial direct current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) on post stroke shoulder pain (PSSP). Methods: We enrolled 13 individuals in this study who underwent three different treatments in a random sequence: active tDCS+active TENS, active tDCS+sham TENS, and sham tDCS+active TENS. Each treatment was administered once, with a 3-day washout period between interventions. A blinded rater assessed the visual analog scale (VAS) scores, fNIRS readings, and sensory and pain tolerance thresholds of the participants before and after the stimulation. Results: All three treatment methods can significantly alleviate PSSP (p<0.05). Compared with using tDCS alone, tDCS+TENS can significantly improve pain, with a statistically significant difference (p<0.05). In the 2KHz PTT task, the three treatment methods showed significant differences (p<0.05) in the mean oxygenated hemoglobin (HbO) levels in the false premotor cortex (PMC)/auxiliary motor area (SMA) before and after intervention. Conclusion: The combination of tDCS+TENS can increase the pain-relieving impact on PSSP when compared to using tDCS alone. TENS may contribute an additional effect on the inhibitory systems influenced by tDCS that help reduce pain. Clinical Registration Number: Registration website: https://www.chictr.org.cn. Registration date: 2022-02-25. Registration number: ChiCTR2200056970.
ABSTRACT
Plants often adapt to adverse or stress conditions via differential growth. The trans-Golgi Network (TGN) has been implicated in stress responses, but it is not clear in what capacity it mediates adaptive growth decisions. In this study, we assess the role of the TGN in stress responses by exploring the interactome of the Transport Protein Particle II (TRAPPII) complex, required for TGN structure and function. We identified physical and genetic interactions between TRAPPII and shaggy-like kinases (GSK3/AtSKs). Kinase assays and pharmacological inhibition provided in vitro and in vivo evidence that AtSKs target the TRAPPII-specific subunit AtTRS120/TRAPPC9. GSK3/AtSK phosphorylation sites in AtTRS120/TRAPPC9 were mutated, and the resulting AtTRS120 phosphovariants subjected to a variety of single and multiple stress conditions in planta . The non-phosphorylatable TRS120 mutant exhibited enhanced adaptation to multiple stress conditions and to osmotic stress whereas the phosphomimetic version was less resilient. Higher order inducible trappii atsk mutants had a synthetically enhanced defect in root gravitropism. Our results suggest that the TRAPPII phosphostatus mediates adaptive responses to abiotic cues. AtSKs are multifunctional kinases that integrate a broad range of signals. Similarly, the TRAPPII interactome is vast and considerably enriched in signaling components. An AtSK-TRAPPII interaction would integrate all levels of cellular organization and instruct the TGN, a central and highly discriminate cellular hub, as to how to mobilize and allocate resources to optimize growth and survival under limiting or adverse conditions.
ABSTRACT
Plant cell expansion is driven by turgor pressure and regulated by hormones. How plant cells avoid cell wall rupture during hormone-induced cell expansion remains a mystery. Here we show that brassinosteroid (BR), while stimulating cell elongation, promotes the plasma membrane (PM) accumulation of the receptor kinase FERONIA (FER), which monitors cell wall damage and in turn attenuates BR-induced cell elongation to prevent cell rupture. The GSK3-like kinase BIN2 phosphorylates FER, resulting in reduced FER accumulation and translocation from endoplasmic reticulum to PM. By inactivating BIN2, BR signaling promotes dephosphorylation and increases PM accumulation of FER, thereby enhancing the surveillance of cell wall integrity. Our study reveals a vital signaling circuit that coordinates hormone signaling with mechanical sensing to prevent cell bursting during hormone-induced cell expansion.
ABSTRACT
Increasing evidence suggests that alternative splicing plays a critical role in pain, but its underlying mechanism remains elusive. Herein, we employed complete Freund's adjuvant (CFA) to induce inflammatory pain in mice. A combination of genomics research techniques, lentivirus-based genetic manipulations, behavioral tests, and molecular biological technologies confirmed that splicing factor Cwc22 mRNA and CWC22 protein were elevated in the spinal dorsal horn at 3 days after CFA injection. Knockdown of spinal CWC22 by lentivirus transfection (lenti-shCwc22) reversed CFA-induced thermal hyperalgesia and mechanical allodynia, whereas upregulation of spinal CWC22 (lenti-Cwc22) in naïve mice precipitated pain. Comprehensive transcriptome and genome analysis identified the secreted phosphoprotein 1 (Spp1) as a potential gene of CWC22-mediated alternative splicing, however, only Spp1 splicing variant 4 (Spp1 V4) was involved in thermal and mechanical nociceptive regulation. In conclusion, our findings demonstrate that spinal CWC22 regulates Spp1 V4 to participate in CFA-induced inflammatory pain. Blocking CWC22 or CWC22-mediated alternative splicing may provide a novel therapeutic target for the treatment of persistent inflammatory pain.
Subject(s)
Alternative Splicing , Nociception , Animals , Mice , Freund's Adjuvant/toxicity , Hyperalgesia/metabolism , Inflammation/metabolism , Osteopontin/metabolism , Pain/drug therapy , Spinal Cord/metabolismABSTRACT
BRASSINAZONE RESISTANT 1 (BZR1) is a key transcription factor of the brassinosteroid signaling pathway but also a signaling hub that integrates diverse signals that modulate plant growth. Previous studies have shown that starvation causes BZR1 degradation, but the underlying mechanisms are not understood. Here we performed quantitative proteomic analysis of BZR1 interactome under starvation conditions and identified two BZR1-interacting ubiquitin ligases, BAF1 and UPL3. Compared to the wild type, the upl3 mutants show long hypocotyl and increased BZR1 levels when grown under sugar starvation conditions but not when grown on sugar-containing media, indicating a role of UPL3 in BZR1 degradation specifically under starvation conditions. The upl3 mutants showed a reduced survival rate after starvation treatment, supporting the importance of UPL3-mediated BZR1 degradation and growth arrest for starvation survival. Treatments with inhibitors of TARGET of RAPAMYCIN (TOR) and autophagy altered BZR1 level in the wild type but were less effective in upl3 , suggesting that UPL3 mediates the TOR-regulated and autophagy-dependent degradation of BZR1. Further, the UPL3 protein level is increased posttranscriptionally by starvation but decreased by sugar treatment. Our study identifies UPL3 as a key component that mediates sugar regulation of hormone signaling pathways, important for optimal growth and survival in plants. IN A NUTSHELL: Background: The coordination between signaling pathways that monitor the levels of photosynthate and growth hormones is crucial for optimizing growth and survival, but the underlying mechanisms are not fully understood. When the sugar level is low, the BZR1 transcription factor of the brassinosteroid (BR) signaling pathway is degraded, and hence growth is attenuated to prevent starvation and enhance survival. When sugar is sufficient, sugar signaling inhibits BZR1 degradation and enables BR promotion of plant growth. The key component that mediates starvation-induced BZR1 degradation remains unknown.Question: What proteins interact with BZR1 and mediate its degradation under sugar starvation?Finding: We performed immunoprecipitation mass spectrometry analysis of BZR1 in starvation-treated Arabidopsis and identified many BZR1-interacting proteins, including two E3 ligases UPL3 and BAF1. Genetic analysis showed that UPL3 plays a specific and prominent role in promoting autophagy-dependent BZR1 degradation and plant survival under sugar-starvation conditions.Next step: How sugar-TOR signaling regulates UPL3 level remains to be studied in the future.