Mitochondrial hypoxic stress induces widespread RNA editing by APOBEC3G in natural killer cells

Abstract

Background 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 and macrophages in response to hypoxia and interferons, the physiological significance of such editing is unclear. Results Here, we show that the related cytidine deaminase, APOBEC3G, induces site-specific C-to-U RNA editing in natural killer cells, lymphoma cell lines, and, to a lesser extent, CD8-positive T cells upon cellular crowding and hypoxia. In contrast to expectations from its anti-HIV-1 function, the highest expression of APOBEC3G is shown to be in cytotoxic lymphocytes. RNA-seq analysis of natural killer cells subjected to cellular crowding and hypoxia reveals widespread C-to-U mRNA editing that is enriched for genes involved in mRNA translation and ribosome function. APOBEC3G promotes Warburg-like metabolic remodeling in 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. Conclusions APOBEC3G is an endogenous RNA editing enzyme in primary natural killer cells and lymphoma cell lines. This RNA editing is induced by cellular crowding and mitochondrial respiratory inhibition to promote adaptation to hypoxic stress. Electronic supplementary material The online version of this article (10.1186/s13059-019-1651-1) contains supplementary material, which is available to authorized users.

RNA editing enzyme APOBEC3A promotes pro-inflammatory (M1) macrophage polarization

“…A3A-or A3G-induced RNA editing by cellular crowding and hypoxia can be mimicked by the inhibition of mitochondrial respiration (Sharma et al, 2017b;Sharma et al, 2019). A3G-mediated RNA editing triggers a Warburg-like metabolic remodeling in HuT78 T cell lymphoma line (Sharma et al, 2019). These findings suggest that APOBEC3-mediated RNA editing may play a role in hypoxia-or IFNinduced cell stress response.…”

“…Such inhibitions may be dependent or independent of the deaminase functions of APOBEC3s (Holmes et al, 2007). Recently, we identified the cellular RNA editing functions of APOBEC3A (A3A) (Sharma et al, 2015) and APOBEC3G (A3G) (Sharma et al, 2019). A3A and A3G each target specific cytidines located in stem-loop structures in distinct set of transcripts (Sharma and Baysal 2017).…”

“…A3A-mediated RNA editing is endogeneously induced by IFN-γ during M1 macrophage polarization and by type 1 interferons (IFN-1) in monocytes/macrophages (Sharma et al, 2015). In addition to IFNs, hypoxia and cellular crowding induces endogenous C>U RNA editing by A3A in monocytes and by A3G in natural killer (NK) cells (Baysal et al, 2013;Sharma et al, 2015;Sharma et al, 2019). Hypoxia and IFN-1 additively enhance A3A-mediated RNA editing in monocytes, leading 6 to RNA editing levels of ~ 80% in transcripts of certain genes.…”

“…Hypoxia and IFN-1 additively enhance A3A-mediated RNA editing in monocytes, leading 6 to RNA editing levels of ~ 80% in transcripts of certain genes. A3A-or A3G-induced RNA editing by cellular crowding and hypoxia can be mimicked by the inhibition of mitochondrial respiration (Sharma et al, 2017b;Sharma et al, 2019). A3G-mediated RNA editing triggers a Warburg-like metabolic remodeling in HuT78 T cell lymphoma line (Sharma et al, 2019).…”

MultiEditR: An easy validation method for detecting and quantifying RNA editing from Sanger sequencing

“…APOBEC1 Cto-U editing seems to have a role also in maintaining brain physiology in mice, rats and humans (Cole et al 2017;Kankowski et al 2018;Meier et al 2005), suggesting a critical role of C-to-U editing in the regulatory mechanism for brain homeostasis (Gagnidze et al 2018). Finally, human APOBEC3A and APOBEC3G were also shown to be able to perform C-to-U RNA editing (Sharma et al 2015(Sharma et al , 2016(Sharma et al , 2017(Sharma et al , 2019, suggesting that in humans, three APOBECs are able to catalyze this epitranscriptomic mark.…”