Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS

Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROSMitochondria manganese superoxide dismutase (SOD2) is a major antioxidant enzyme associated with several diseases. This study shows that SOD2 is inhibited by acetylation and activated by SIRT3-mediated deacetylation in response to reactive oxygen species (ROS).Mitochondria manganese superoxide dismutase (SOD2) is an important antioxidant enzyme, deficiency of which is associated with various human diseases. The known primary regulation of SOD2 is through transcriptional activation. Here, we report that SOD2 is acetylated at Lys 68 and that this acetylation decreases SOD2 activity. Mitochondrial deacetylase SIRT3 binds to, deacetylates and activates SOD2. Increase of reactive oxygen species (ROS) levels stimulates SIRT3 transcription, leading to SOD2 deacetylation and activation. SOD2-mediated ROS reduction is synergistically increased by SIRT3 co-expression, but is cancelled by SIRT3 depletion. These results reveal a new post-translational regulation of SOD2 by means of acetylation and SIRT3-dependent deacetylation in response to oxidative stress

Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase

Protein acetylation has emerged as a major mechanism in regulating cellular metabolism. Whereas most glycolytic steps are reversible, the reaction catalyzed by pyruvate kinase is irreversible and the reverse reaction requires phosphoenolpyruvate carboxykinase (PEPCK1) to commit for gluconeogenesis. Here we show that acetylation regulates the stability of the gluconeogenic rate limiting enzyme PEPCK1, thereby modulating cellular response to glucose. High glucose destabilizes PEPCK1 by stimulating its acetylation. PEPCK1 is acetylated by the P300 acetyltransferase and this acetylation stimulates the interaction between PEPCK1 and UBR5, a HECT domain containing E3 ubiquitin ligase, therefore promoting PEPCK1 ubiquitinylation and degradation. Conversely, SIRT2 deacetylates and stabilizes PEPCK1. These observations represent an example that acetylation targets a metabolic enzyme to a specific E3 ligase in response to metabolic condition changes. Given that increased levels of PEPCK is linked with type II diabetes, this study also identifies potential therapeutic targets for diabetes

Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema

Angioedema occurring in the head and neck region is a rare and sometimes life‐threatening adverse reaction to angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI‐induced angioedema (ACEI‐AE) or ARB‐induced angioedema (ARB‐AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI‐AE, ARB‐AE, and 658 controls) was performed using exome‐enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI‐AE and ARB‐AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89–4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI‐AE or ARB‐AE, P = 2.09 × 10−3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49–3.27, P = 6.30 × 10−9) times the odds of having ACEI‐AE or ARB‐AE. The increased risk due to the common Leiden allele was confirmed in a genome‐wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect‐causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI‐AE or ARB‐AE

Response of ecosystem services and environmental dynamics in large open-pit coal mines: A case study in semi-arid areas

Surface coal mining in semi-arid regions has detrimental impacts on the structure and function of surface ecosystems, thereby impeding the attainment of regional sustainable development goals. Moreover, the impact of climate change on ecological restoration in semi-arid mining areas is an inevitable consideration. To elucidate the response of ecosystem services in mining areas to regional climate change, topography, soil, vegetation and socioeconomic development, this study selected six large-scale surface coal mines located in semi-arid regions of China as research objects. In this study, we aimed to assess the main ecosystem services (carbon sequestration, soil conservation, and flow regulation) provided by these mines. In addition, we analysed the spatial and temporal evolution and interrelationships of these ecosystem services. Furthermore, we explored the underlying mechanisms between ecosystem services and environmental factors. The results showed the following: (1) Geospatially, there was a gradual decrease in carbon sequestration and flow regulation from northeast to southwest in the mining areas. However, the soil conservation exhibited an upward trend. Throughout the research period, the carbon sequestration change rate in the six mining areas displayed an initial downward and subsequent upward trend, the rate of soil conservation exhibited a gradual upward trend, and the flow regulation decline rate followed a downward trend. (2) Change rate of carbon sequestration and soil conservation in the six mining areas showed a significant positive correlation (r = 0.51, p < 0.001), with the strongest correlation observed in the Shengli Mining Area (r = 0.64, p < 0.001). (3) Ecosystem service changes in the mining areas were primarily driven by initial conditions (95.0%), followed by meteorological factors (4.2%). Three ecological restoration models were proposed for the different regions based on driver analyses. The findings of this study offer scientific evidence that can be used to inform ecological management, enhance ecological security, and promote regional sustainable development in mining areas

Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS

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Lysine 88 Acetylation Negatively Regulates Ornithine Carbamoyltransferase Activity in Response to Nutrient Signals*

Ornithine carbamoyltransferase (OTC) is a key enzyme in the urea cycle to detoxify ammonium produced from amino acid catabolism. OTC deficiency is an X-linked genetic disorder ranging from fatal in newborns to hyperammonemia and anorexia in adults. Through affinity purification of acetylated peptides and mass spectrometry, we identified that OTC is acetylated on lysine residues, including Lys88, which is also mutated in OTC-deficient patients. OTC acetylation was confirmed to occur under physiological conditions. Biochemical characterizations revealed that OTC Lys88 acetylation decreases the affinity for carbamoyl phosphate, one of the two OTC substrates, and the maximum velocity, whereas the Km for ornithine, the other OTC substrate, is not affected. Furthermore, Lys88 acetylation is regulated by both extracellular glucose and amino acid availability, indicating that OTC activity may be regulated by cellular metabolic status. Our results provide an example of the novel mechanism of regulating metabolic enzyme activity through protein acetylation

Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase

Protein acetylation has emerged as a major mechanism in regulating cellular metabolism. Whereas most glycolytic steps are reversible, the reaction catalyzed by pyruvate kinase is irreversible and the reverse reaction requires phosphoenolpyruvate carboxykinase (PEPCK1) to commit for gluconeogenesis. Here we show that acetylation regulates the stability of the gluconeogenic rate limiting enzyme PEPCK1, thereby modulating cellular response to glucose. High glucose destabilizes PEPCK1 by stimulating its acetylation. PEPCK1 is acetylated by the P300 acetyltransferase and this acetylation stimulates the interaction between PEPCK1 and UBR5, a HECT domain containing E3 ubiquitin ligase, therefore promoting PEPCK1 ubiquitinylation and degradation. Conversely, SIRT2 deacetylates and stabilizes PEPCK1. These observations represent an example that acetylation targets a metabolic enzyme to a specific E3 ligase in response to metabolic condition changes. Given that increased levels of PEPCK is linked with type II diabetes, this study also identifies potential therapeutic targets for diabetes

Study of the Integrated Immune Response Induced by an Inactivated EV71 Vaccine

<div><p>Enterovirus 71 (EV71), a major causative agent of hand-foot-and-mouth disease (HFMD), causes outbreaks among children in the Asia-Pacific region. A vaccine is urgently needed. Based on successful pre-clinical work, phase I and II clinical trials of an inactivated EV71 vaccine, which included the participants of 288 and 660 respectively, have been conducted. In the present study, the immune response and the correlated modulation of gene expression in the peripheral blood mononuclear cells (PBMCs) of 30 infants (6 to 11 months) immunized with this vaccine or placebo and consented to join this study in the phase II clinical trial were analyzed. The results showed significantly greater neutralizing antibody and specific T cell responses in vaccine group after two inoculations on days 0 and 28. Additionally, more than 600 functional genes that were up- or down-regulated in PBMCs were identified by the microarray assay, and these genes included 68 genes associated with the immune response in vaccine group. These results emphasize the gene expression profile of the immune system in response to an inactivated EV71 vaccine in humans and confirmed that such an immune response was generated as the result of the positive mobilization of the immune system. Furthermore, the immune response was not accompanied by the development of a remarkable inflammatory response.</p> <p> <em>Clinical Trial Registration: NCT01391494 and NCT01512706.</em></p> </div

Vaccination with the inactivated EV71 vaccine modulated gene expression.

<p>A global view of gene modulation in the PBMCs of vaccinated infants (Vac, n = 20), 28 days after the vaccine booster, compared to the placebo cohort (Pla, n = 10) was determined by microarray analysis. The genes were classified according to their function. A heat map representation (a) and principal component analysis (PCA) (b) generated using the significantly modulated genes from at least one comparison versus day 0 are shown. (a) The color scale shows the significantly modulated genes from up- (dark red) to down-regulated (dark blue) to the right of each image. The values are shown on a log₂ scale. (b) The Y value is the log₂-fold-changes in gene expression of the vaccinated group vs. the placebo group. The up-regulated changes are above the baseline (Y = 0, the same with placebo group), and the down-regulated changes are below the baseline. The bars represent the maximum and minimum. The mean of the fold-changes in gene expression with a 95% CI is shown as the rectangle. The line in the rectangle represents the mean of these fold changes in gene expression. The number of genes that changed after immunization is shown beside the rectangles on the image.</p

Immune responses were induced by the inactivated EV71 vaccine.

<p>The humoral (a) and cellular immune responses (b) against EV71 antigen were induced by the inactivated EV71 vaccine in volunteers (n = 20 for Vaccinated and n = 10 for Placebo). (a) The neutralizing antibodies targeting the EV71 antigen in the serum of experimental subjects. The geometric mean titers (GMTs) of neutralizing antibodies to EV71 were measured by a neutralization test as described in the Methods. **, P values of vaccinated group vs baseline value (at 0 day before primary immunization) and vs placebo group were <0.01. (b) The specific T cell response to EV71 antigenic peptides (sequences described in result section), as determined by an Elispot assay. PBMCs from the experimental subjects were incubated in the presence of 10 µM peptides, as described in the Methods section. The values are expressed as the mean±S.D. (n = 20 for Vaccinated and n = 10 for Placebo). **, P values of vaccinated group vs baseline value (at 0 day before primary immunization) and vs placebo group were <0.01. (c) The inactivated EV71 vaccination induces multiple arms of the innate and adaptive responses. Heat map of significantly modulated genes associated with immune responses against the EV71 antigen were analyzed on vaccinated cohort (Vac, n = 20) compared placebo cohort (Pla, n = 10). The listed genes were fallen under different functional categories, which included classification associated with activation of T cell, B cell, innate response adaptive response and MHC respectively. The values are shown in log₂ scale.</p