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Heat stress induces misfolding and aggregation of proteins unless they are guarded by chaperone systems. Here, we examined the function of the glutaredoxin GRXS17, a member of thiol reductase families in the model plant Arabidopsis ( Arabidopsis thaliana ). GRXS17 is a nucleocytosolic monothiol glutaredoxin consisting of an N-terminal thioredoxin domain and three CGFS active-site motif-containing GRX domains that coordinate three iron-sulfur (Fe-S) clusters in a glutathione-dependent manner. As an Fe-S cluster-charged holoenzyme, GRXS17 is likely involved in the maturation of cytosolic and nuclear Fe-S proteins. In addition to its role in cluster biogenesis, GRXS17 presented both foldase and redox-dependent holdase activities. Oxidative stress in combination with heat stress induced loss of its Fe-S clusters followed by subsequent formation of disulfide bonds between conserved active-site cysteines in the corresponding thioredoxin domains. This oxidation led to a shift of GRXS17 to a high-molecular-weight complex and thus activated its holdase activity in vitro. Moreover, GRXS17 was specifically involved in plant tolerance to moderate high temperature and protected root meristematic cells from heat-induced cell death. Finally, GRXS17 interacted with a different set of proteins upon heat stress, possibly protecting them from heat injuries. Therefore, we propose that the Fe-S cluster enzyme GRXS17 is an essential guard that protects proteins against moderate heat stress, likely through a redox-dependent chaperone activity. We reveal the mechanism of an Fe-S cluster-dependent activity shift that converts the holoenzyme GRXS17 into a holdase, thereby preventing damage caused by heat stress., (© 2020 American Society of Plant Biologists. All Rights Reserved.)

Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways. RNA-sequencing of adipose tissue macrophages demonstrated a role for miR-146a in regulating both inflammation and cellular metabolism, including the mTOR pathway, during obesity. Further, we demonstrate that miR-146a regulates inflammation, cellular respiration and glycolysis in macrophages through a mechanism involving its direct target Traf6. Finally, we found that administration of rapamycin, an inhibitor of mTOR, was able to rescue the obesity phenotype in miR-146a-/- mice. Altogether, our study provides evidence that miR-146a represses inflammation and diet-induced obesity and regulates metabolic processes at the cellular and organismal levels, demonstrating how the combination of diet and miRNA genetics influences obesity and diabetic phenotypes., Competing Interests: The authors have declared that no competing interests exist.

Some of the most challenging stress conditions that organisms encounter during their lifetime involve the transient accumulation of reactive oxygen and chlorine species. Extremely reactive to amino acid side chains, these oxidants cause widespread protein unfolding and aggregation. It is therefore not surprising that cells draw on a variety of different strategies to counteract the damage and maintain a healthy proteome. Orchestrated largely by direct changes in the thiol oxidation status of key proteins, the response strategies involve all layers of protein protection. Reprogramming of basic biological functions helps decrease nascent protein synthesis and restore redox homeostasis. Mobilization of oxidative stress-activated chaperones and production of stress-resistant non-proteinaceous chaperones prevent irreversible protein aggregation. Finally, redox-controlled increase in proteasome activity removes any irreversibly damaged proteins. Together, these systems pave the way to restore protein homeostasis and enable organisms to survive stress conditions that are inevitable when living an aerobic lifestyle., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Proteins are constantly challenged by environmental stress conditions that threaten their structure and function. Especially problematic are oxidative, acid, and severe heat stress which induce very rapid and widespread protein unfolding and generate conditions that make canonical chaperones and/or transcriptional responses inadequate to protect the proteome. We review here recent advances in identifying and characterizing stress-activated chaperones which are inactive under non-stress conditions but become potent chaperones under specific protein-unfolding stress conditions. We discuss the post-translational mechanisms by which these chaperones sense stress, and consider the role that intrinsic disorder plays in their regulation and function. We examine their physiological roles under both non-stress and stress conditions, their integration into the cellular proteostasis network, and their potential as novel therapeutic targets., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The commensal microbiota has an important impact on host health, which is only beginning to be elucidated. Despite the presence of fungal, archaeal, and viral members, most studies have focused solely on the bacterial microbiota. Antibodies against the yeast Saccharomyces cerevisiae are found in some patients with Crohn's disease (CD), suggesting that the mycobiota may contribute to disease severity. We report that S. cerevisiae exacerbated intestinal disease in a mouse model of colitis and increased gut barrier permeability. Transcriptome analysis of colon tissue from germ-free mice inoculated with S. cerevisiae or another fungus, Rhodotorula aurantiaca , revealed that S. cerevisiae colonization affected the intestinal barrier and host metabolism. A fecal metabolomics screen of germ-free animals demonstrated that S. cerevisiae colonization enhanced host purine metabolism, leading to an increase in uric acid production. Treatment with uric acid alone worsened disease and increased gut permeability. Allopurinol, a clinical drug used to reduce uric acid, ameliorated colitis induced by S. cerevisiae in mice. In addition, we found a positive correlation between elevated uric acid and anti-yeast antibodies in human sera. Thus, yeast in the gut may be able to potentiate metabolite production that negatively affects the course of inflammatory bowel disease., (Copyright © 2017, American Association for the Advancement of Science.)

Background: A plethora of valves and valve conduits are available for reconstruction of the right ventricular outflow tract (RVOT) for grown-up congenital heart patients. However, for several reasons, the ideal pulmonary valve substitute still remains the subject of debate. In this study, we investigated the preliminary clinical and echocardiographic results after implantation of the RVOT Elan (Vascutek, Renfrewshire, United Kingdom) conduit in adolescents and adults., Material and Methods: Between October 2012 and December 2014, a total of 27 patients (19 males, mean age: 23.7 ± 22.5; range: 9-74 years) received a RVOT Elan conduit for RVOT reconstruction and were prospectively followed up clinically and echocardiographically. Twenty-five patients had previous cardiac surgery. The median number of prior operations per patient was 2 (range: 1-4). Tetralogy of Fallot was the most common diagnosis (n = 7)., Results: At a mean follow-up time of 0.9 ± 0.61 years (100% complete), all patients (27 of 27) were alive and in New York Heart Association Class I. Adverse events defined as valve failure, thrombosis, embolism, bleeding, or endocarditis did not occur. Freedom from reoperation in general was 100%. At 1-year follow-up, median peak pressure gradients (Δ Pmax) across the RVOT Elan conduit were 15 ± 3.2; 15.3 ± 2.1Δ, 16 ± 4.8, and 16.3 ± 5.1 mm Hg for the 19 (n = 3), 21 (n = 3), 23 (n = 6), and 25 mm (n = 15) conduit size, respectively., Conclusion: The RVOT Elan conduit revealed excellent preliminary clinical and hemodynamic performances independent from the underlying cardiac pathology with insignificant transvalvular gradients and nonturbulent flow characteristics., (Georg Thieme Verlag KG Stuttgart · New York.)

An anomalous origin of the left circumflex coronary artery that arises as a side branch of the right coronary artery from the right coronary sinus of Valsalva encircling the aortic annulus is usually an incidental finding. However, in patients undergoing aortic valve procedures, its existence can significantly complicate the surgical treatment. We report our operative strategy in patients with an anomalous left circumflex coronary artery, a bicuspid aortic valve morphology and different aortic valve pathologies., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Exposure of cells to reactive oxygen species (ROS) causes a rapid and significant drop in intracellular ATP levels. This energy depletion negatively affects ATP-dependent chaperone systems, making ROS-mediated protein unfolding and aggregation a potentially very challenging problem. Here we show that Get3, a protein involved in ATP-dependent targeting of tail-anchored (TA) proteins under nonstress conditions, turns into an effective ATP-independent chaperone when oxidized. Activation of Get3's chaperone function, which is a fully reversible process, involves disulfide bond formation, metal release, and its conversion into distinct, higher oligomeric structures. Mutational studies demonstrate that the chaperone activity of Get3 is functionally distinct from and likely mutually exclusive with its targeting function, and responsible for the oxidative stress-sensitive phenotype that has long been noted for yeast cells lacking functional Get3. These results provide convincing evidence that Get3 functions as a redox-regulated chaperone, effectively protecting eukaryotic cells against oxidative protein damage., (Copyright © 2014 Elsevier Inc. All rights reserved.)