Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration.     

Dynamic Ubiquitination of the Mitogen-activated Protein Kinase Kinase (MAPKK) Ste7 Determines Mitogen-activated Protein Kinase (MAPK) Specificity

Ubiquitination is a post-translational modification that tags proteins for proteasomal degradation. In addition, there is a growing appreciation that ubiquitination can influence protein activity and localization. Ste7 is a prototype MAPKK in yeast that participates in both the pheromone signaling and nutrient deprivation/invasive growth pathways. We have shown previously that Ste7 is ubiquitinated upon pheromone stimulation. Here, we show that the Skp1/Cullin/F-box ubiquitin ligase SCF^Cdc4 and the ubiquitin protease Ubp3 regulate Ste7 ubiquitination and signal specificity. Using purified components, we demonstrate that SCF^Cdc4 ubiquitinates Ste7 directly. Using gene deletion mutants, we show that SCF^Cdc4 and Ubp3 have opposing effects on Ste7 ubiquitination. Although SCF^Cdc4 is necessary for proper activation of the pheromone MAPK Fus3, Ubp3 is needed to limit activation of the invasive growth MAPK Kss1. Finally, we show that Fus3 phosphorylates Ubp3 directly and that phosphorylation of Ubp3 is necessary to limit Kss1 activation. These results reveal a feedback loop wherein one MAPK limits the ubiquitination of an upstream MAPKK and thereby prevents spurious activation of a second competing MAPK.     

Mechanisms of Nitrosylation and Denitrosylation of Cytoplasmic Glyceraldehyde-3-phosphate Dehydrogenase from Arabidopsis thaliana

Nitrosylation is a reversible post-translational modification of protein cysteines playing a major role in cellular regulation and signaling in many organisms, including plants where it has been implicated in the regulation of immunity and cell death. The extent of nitrosylation of a given cysteine residue is governed by the equilibrium between nitrosylation and denitrosylation reactions. The mechanisms of these reactions remain poorly studied in plants. In this study, we have employed glycolytic GAPDH from Arabidopsis thaliana as a tool to investigate the molecular mechanisms of nitrosylation and denitrosylation using a combination of approaches, including activity assays, the biotin switch technique, site-directed mutagenesis, and mass spectrometry. Arabidopsis GAPDH activity was reversibly inhibited by nitrosylation of catalytic Cys-149 mediated either chemically with a strong NO donor or by trans-nitrosylation with GSNO. GSNO was found to trigger both GAPDH nitrosylation and glutathionylation, although nitrosylation was widely prominent. Arabidopsis GAPDH was found to be denitrosylated by GSH but not by plant cytoplasmic thioredoxins. GSH fully converted nitrosylated GAPDH to the reduced, active enzyme, without forming any glutathionylated GAPDH. Thus, we found that nitrosylation of GAPDH is not a step toward formation of the more stable glutathionylated enzyme. GSH-dependent denitrosylation of GAPC1 was found to be linked to the [GSH]/[GSNO] ratio and to be independent of the [GSH]/[GSSG] ratio. The possible importance of these biochemical properties for the regulation of Arabidopsis GAPDH functions in vivo is discussed.     

Gravel dredging alters diversity and structure of riverine fish assemblages

1. Human activities affect fish assemblages in a variety of ways. Large‐scale and long‐term disturbances such as in‐stream dredging and mining alter habitat and hydrodynamic characteristics within rivers which can, in turn, alter fish distribution. Habitat heterogeneity is decreased as the natural riffle–pool–run sequences are lost to continuous pools and, as a consequence, lotic species are displaced by lentic species, while generalist and invasive species displace native habitat specialists. Sediment and organic detritus accumulate in deep, dredged reaches and behind dams, disrupting nutrient flow and destroying critical habitat for habitat specialist species. 2. We used standard ecological metrics such as species richness and diversity, as well as stable isotope analysis of δ¹³C and δ¹⁵N, to quantify the differences in fish assemblages sampled by benthic trawls among dredged and undredged sites in the Allegheny River, Pennsylvania, U.S.A. 3. Using mixed‐effects models, we found that total catch, species richness and diversity were negatively correlated with depth (P < 0.05), while species richness, diversity and proportion of species in lithophilic (‘rock‐loving’) reproductive guilds were lower at dredged than at undredged sites (P < 0.05). 4. Principal components analysis and manova revealed that taxa such as darters in brood hider and substratum chooser reproductive guilds were predominantly associated with undredged sites along principal component axis 1 (PC1 and manova P < 0.05), while nest spawners such as catfish and open substratum spawners including suckers were more associated with dredged sites along PC2 (P < 0.05). 5. Stable isotope analysis of δ¹³C and δ¹⁵N revealed shifts from reliance on shallow water and benthic‐derived nutrients at undredged sites to reliance on phytoplankton and terrestrial detritus at deep‐water dredged sites. Relative trophic positions were also lower at dredged sites for many species; loss of benthic nutrient pathways associated with depth and dredging history is hypothesised. 6. The combination of ecological metrics and stable isotope analysis thus shows how anthropogenic habitat loss caused by gravel dredging can decrease benthic fish abundance and diversity, and that species in substratum‐specific reproductive guilds are at particular risk. The effects of dredging also manifest by altering resource use and nutrient pathways within food webs. Management and conservation decisions should therefore consider the protection of relatively shallow areas with suitable substratum for spawning for the protection of native fishes.     

Biotechnological implications from abscisic acid (ABA) roles in cold stress and leaf senescence as an important signal for improving plant sustainable survival under abiotic-stressed conditions

In the past few years, the signal transduction of the plant hormone abscisic acid (ABA) has been studied extensively and has revealed an unanticipated complex. ABA, characterized as an intracellular messenger, has been proven to act a critical function at the heart of a signaling network operation. It has been found that ABA plays an important role in improving plant tolerance to cold, as well as triggering leaf senescence for years. In addition, there have been many reports suggesting that the signaling pathways for leaf senescence and plant defense responses may overlap. Therefore, the objective was to review what is known about the involvement of ABA signaling in plant responses to cold stress and regulation of leaf senescence. An overview about how ABA is integrated into sugars and reactive oxygen species signaling pathways, to regulate plant cold tolerance and leaf senescence, is provided. These roles can provide important implications for biotechnologically improving plant cold tolerance.     

SEASONALITY MAINTAINS ALTERNATIVE LIFE‐HISTORY PHENOTYPES

Many organisms express discrete alternative phenotypes (polyphenisms) in relation to predictable environmental variation. However, the evolution of alternative life‐history phenotypes remains poorly understood. Here, we analyze the evolution of alternative life histories in seasonal environments by using temperate insects as a model system. Temperate insects express alternative developmental pathways of diapause and direct development, the induction of a certain pathway affecting fitness through its life‐history correlates. We develop a methodologically novel and holistic simulation model and optimize development time, growth rate, body size, reproductive effort, and adult life span simultaneously in both developmental pathways. The model predicts that direct development should be associated with shorter development time (duration of growth) and adult life span, higher growth rate and reproductive effort, smaller body size as well as lower fecundity compared to the diapause pathway, because the two generations divide the available time unequally. These predictions are consistent with many empirical data. Our analysis shows that seasonality alone can explain the evolution of alternative life histories.     

Five Conditions Commonly Used to Down-regulate Tor Complex 1 Generate Different Physiological Situations Exhibiting Distinct Requirements and Outcomes

Five different physiological conditions have been used interchangeably to establish the sequence of molecular events needed to achieve nitrogen-responsive down-regulation of TorC1 and its subsequent regulation of downstream reporters: nitrogen starvation, methionine sulfoximine (Msx) addition, nitrogen limitation, rapamycin addition, and leucine starvation. Therefore, we tested a specific underlying assumption upon which the interpretation of data generated by these five experimental perturbations is premised. It is that they generate physiologically equivalent outcomes with respect to TorC1, i.e. its down-regulation as reflected by TorC1 reporter responses. We tested this assumption by performing head-to-head comparisons of the requirements for each condition to achieve a common outcome for a downstream proxy of TorC1 inactivation, nuclear Gln3 localization. We demonstrate that the five conditions for down-regulating TorC1 do not elicit physiologically equivalent outcomes. Four of the methods exhibit hierarchical Sit4 and PP2A phosphatase requirements to elicit nuclear Gln3-Myc¹³ localization. Rapamycin treatment required Sit4 and PP2A. Nitrogen limitation and short-term nitrogen starvation required only Sit4. G₁ arrest-correlated, long-term nitrogen starvation and Msx treatment required neither PP2A nor Sit4. Starving cells of leucine or treating them with leucyl-tRNA synthetase inhibitors did not elicit nuclear Gln3-Myc¹³ localization. These data indicate that the five commonly used nitrogen-related conditions of down-regulating TorC1 are not physiologically equivalent and minimally involve partially differing regulatory mechanisms. Further, identical requirements for Msx treatment and long-term nitrogen starvation raise the possibility that their effects are achieved through a common regulatory pathway with glutamine, a glutamate or glutamine metabolite level as the sensed metabolic signal.     

Increase in Serum Ca2+/Mg2+ Ratio Promotes Proliferation of Prostate Cancer Cells by Activating TRPM7 Channels

TRPM7 is a novel magnesium-nucleotide-regulated metal current (MagNuM) channel that is regulated by serum Mg²⁺ concentrations. Changes in Mg²⁺ concentration have been shown to alter cell proliferation in various cells; however, the mechanism and the ion channel(s) involved have not yet been identified. Here we demonstrate that TRPM7 is expressed in control and prostate cancer cells. Supplementation of intracellular Mg-ATP or addition of external 2-aminoethoxydiphenyl borate inhibited MagNuM currents. Furthermore, silencing of TRPM7 inhibited whereas overexpression of TRPM7 increased endogenous MagNuM currents, suggesting that these currents are dependent on TRPM7. Importantly, although an increase in the serum Ca²⁺/Mg²⁺ ratio facilitated Ca²⁺ influx in both control and prostate cancer cells, a significantly higher Ca²⁺ influx was observed in prostate cancer cells. TRPM7 expression was also increased in cancer cells, but its expression was not dependent on the Ca²⁺/Mg²⁺ ratio per se. Additionally, an increase in the extracellular Ca²⁺/Mg²⁺ ratio led to a significant increase in cell proliferation of prostate cancer cells when compared with control cells. Consistent with these results, age-matched prostate cancer patients also showed a subsequent increase in the Ca²⁺/Mg²⁺ ratio and TRPM7 expression. Altogether, we provide evidence that the TRPM7 channel has an important role in prostate cancer and have identified that the Ca²⁺/Mg²⁺ ratio could be essential for the initiation/progression of prostate cancer.