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Mitochondrial hypoxic stress induces RNA editing by APOBEC3G in lymphocytes

ABSTRACT: Protein recoding by RNA editing is required for normal health and evolutionary adaptation. However, de novo induction of RNA editing in response to environmental factors is an uncommon phenomenon. While APOBEC3A edits many mRNAs in monocytes/macrophages in response to hypoxia and interferons, the physiological significance of such editing is unclear. Here we show that the related APOBEC3G cytidine deaminase induces site-specific C-to-U RNA editing in natural killer (NK), CD8+ T cells and lymphoma cell lines upon cellular crowding and hypoxia. RNA seq analysis of hypoxic NK cells reveals C-to-U recoding mRNA editing in dozens of genes including multiple translational and ribosomal genes. APOBEC3G promotes Warburg-like metabolic remodeling and reduces proliferation of HuT78 T cells under similar conditions. Hypoxia-induced RNA editing by APOBEC3G can be mimicked by the inhibition of mitochondrial respiration, and occurs independently of HIF-1α. Thus, APOBEC3G induces mRNA editing in lymphocytes to promote adaptation to mitochondrial hypoxic stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114519 | GEO | 2018/11/22

REPOSITORIES: GEO

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Mitochondrial hypoxic stress induces RNA editing by APOBEC3G in lymphocytes

Project description:Mitochondrial hypoxic stress induces RNA editing by APOBEC3G in lymphocytes

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The RNA editing enzyme ADAR1 is a key regulatory of innate immune responses to RNA

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2014-12-19 | E-GEOD-62917 | biostudies-arrayexpress

Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α

Project description:Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining in situ metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF-1a as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD+) levels. The HIF-1a/NAD+ axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steadystate conditions. In contrast, in activated NK cells under hypoxia, HIF-1a is required for glycolysis, and forced HIF-1a expression boosts glycolysis and NK cell performance in vitro and in vivo. Our data highlight two distinct pathways by which HIF-1a interferes with NK cell metabolism. While HIF-1a-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1a-dependent tryptophan/NAD+ metabolism. Linked cross omic data sets:RNA-seq data associated with this study are available in ArrayExpress (BioStudies): accession <a href='https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-12082' rel='noopener noreferrer' target='_blank'>E-MTAB-12082</a>.

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Project description:Hypoxic stress is a feature of rapidly growing thyroid tumors. Cancer progression is thought to be driven by reactive oxygen species (ROS) induced hypoxia adaptation. NADPH oxidases (NOXs), which produce ROS as their primary and sole function, has become of particular interest in thyroid malignancy. NOX4 was demonstrated to be upregulated in papillary thyroid cancers, functioning as a mitochondrial energetic sensor to modulate ATP levels, mediating overproduction of ROS induced by IL-δ, inversely correlating to thyroid differentiation. In this study, we analyzed hypoxia-treated BCPAP cells transfected with siRNA against NOX4. Results provides insight into the role of NOX4 in hypoxia adaptation.

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Trade-off between transcriptome plasticity and genome evolution in cephalopods

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2017-04-11 | PXD005827 | Pride

Mitochondrial deficiency impairs hypoxic induction of HIF-1 transcriptional activity and retards tumor growth

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2017-01-01 | GSE80320 | GEO

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Project description:In the site of infection, the human fungal pathogen Aspergillus fumigatus faces dynamic changes in oxygen concentrations. The ability to survive in severely hypoxic environments during host invasion is one of important virulence traits of A. fumigatus. Therefore, investigation of hypoxia adaptation mechanisms of this pathogen may suggest potential targets for the development of antifungal therapies. Currently, an increasing number of reports has demonstrated that elevated production of intracellular reactive oxygen species (ROS) under low oxygen conditions plays a regulatory role in modulating cellular responses for adaptation to hypoxia. Our results confirmed raised amounts of intracellular ROS in A. fumigatus exposed to decreased oxygen levels. Moreover, nuclear accumulation of the oxidative stress response transcriptional factor AfYap1 was observed after two hours of low oxygen cultivation. For further analysis, we applied iodo-TMT labeling of redox-sensitive cysteine residues to identify proteins, which get reversibly oxidized and therefore regulated by hypoxic ROS after shifting oxygen content in the culture from 21% to 0.2%. For instance, proteins with important roles in maintaining redox balance and protein folding were modified after one hour of hypoxic cultivation. Redox proteomic investigation also revealed that a mitochondrial protein, designated as Coa6, was regulated by hypoxic ROS. A homologous protein in Saccharomyces cerevisiae was shown to be important for a respiratory chain complex IV assembly. Deletion of the gene encoding this protein in A. fumigatus resulted in complete absence of hypoxic growth, suggesting the significance of complex IV during adaptation of A. fumigatus to oxygen limiting conditions.

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