Aerobic glycolysis (the Warburg effect) is a metabolic hallmark of activated T cells, and has been implicated in augmenting effector T cell responses including expression of the pro-inflammatory cytokine interferon (IFN)-γ via 3′ untranslated region (3′UTR)-mediated mechanisms. Here we show that lactate dehydrogenase A (LDHA) is induced in activated T cells to support aerobic glycolysis, but promotes IFN-γ expression independently of its 3′UTR. Instead, LDHA maintains high levels of acetyl-CoA to enhance histone acetylation and transcription of Ifng. Ablation of LDHA in T cells protects mice from immunopathology triggered by excessive IFN-γ expression or deficiency of regulatory T cells. These findings reveal an epigenetic mechanism by which aerobic glycolysis promotes effector T cell differentiation, and suggest that LDHA may be targeted therapeutically in autoinflammtory diseases.
After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p<0.01 and p<0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (p<0.05), but no differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after transplant.
Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer’s disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.
Edited by M. J. van Raaij, Centro Nacional de Biotecnología -CSIC, Spain Keywords: indoleamine 2,3-dioxygenase 1; cancer immunotherapy; heme proteins; tryptophan metabolism; crystal engineering.PDB references: indoleamine 2,3-dioxygenase 1, complex with epacadostat, 6e40; complex with sulfur analog of epacadostat, 6e41; complex with 4-chlorophenyl imidazole, 6e42; complex with anolog of BMS-978587, 6e43; free enzyme (ferric), 6e44; free enzyme (ferrous), 6e45; complex with tryptophan (ferrous), 6e46Supporting information: this article has supporting information at journals.iucr.org/f High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form
Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of large heterochromatin domains. We further determined the crystal structure of an H3K9M peptide in complex with human H3K9 methyltransferase G9a and SAM, which reveales that the methionine side chain had enhanced van der Waals interactions with G9a. Therefore, our results provide a detailed mechanism by which H3K9M regulates H3K9 methylation.DOI: http://dx.doi.org/10.7554/eLife.17903.001
Radiofrequency (RF) ablation (RFA) is a minimally invasive treatment for colorectal-cancer liver metastases (CLM) in selected nonsurgical patients. Unlike surgical resection, RFA is not followed by routine pathological examination of the target tumor and the surrounding liver tissue. The aim of this study was the evaluation of apoptotic events after RFA. Specifically, we evaluated YO-PRO-1 (YP1), a green fluorescent DNA marker for cells with compromised plasma membrane, as a potential, early marker of cell death. YP1 was applied on liver tissue adherent on the RF electrode used for CLM ablation, as well as on biopsy samples from the center and the margin of the ablation zone as depicted by dynamic CT immediately after RFA. Normal pig and mouse liver tissues were used for comparison. The same samples were also immunostained for fragmented DNA (TUN-EL assay) and for active mitochondria (anti-OxPhos antibody). YP1 was also used simultaneously with propidium iodine (PI) to stain mouse liver and samples from ablated CLM. Following RFA of human CLM, more than 90 % of cells were positive for YP1. In nonablated, dissected pig and mouse liver however, we found similar YP1 signals (93.1 % and 65 %, respectively). In samples of intact mouse liver parenchyma, there was a significantly smaller proportion of YP1 positive cells (22.7 %). YP1 and PI staining was similar for ablated CLM. However in dissected normal mouse liver there was initial YP1 positivity and complete absence of the PI signal and only later there was PI signal. Conclusion: This is the first time that YP1 was applied in liver parenchymal tissue (rather than cell culture). The results suggest that YP1 is a very sensitive marker of early cellular events reflecting an early and widespread plasma membrane injury that allows YP1 penetration into the cells.
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