ARE-mediated decay controls gene expression and cellular metabolism upon oxygen variations

Abstract

Hypoxia triggers profound modifications of cellular transcriptional programs. Upon reoxygenation, cells return to a normoxic gene expression pattern and mRNA produced during the hypoxic phase are degraded. TIS11 proteins control deadenylation and decay of transcripts containing AU-rich elements (AREs). We observed that the level of dTIS11 is decreased in hypoxic S2 Drosophila cells and returns to normal level upon reoxygenation. Bioinformatic analyses using the ARE-assessing algorithm AREScore show that the hypoxic S2 transcriptome is enriched in ARE-containing transcripts and that this trend is conserved in human myeloid cells. Moreover, an efficient down-regulation of Drosophila ARE-containing transcripts during hypoxia/normoxia transition requires dtis11 expression. Several of these genes encode proteins with metabolic functions. Here, we show that ImpL3 coding for Lactate Dehydrogenase in Drosophila, is regulated by ARE-mediated decay (AMD) with dTIS11 contributing to ImpL3 rapid down-regulation upon return to normal oxygen levels after hypoxia. More generally, we observed that dtis11 expression contributes to cell metabolic and proliferative recovery upon reoxygenation. Altogether, our data demonstrate that AMD plays an important role in the control of gene expression upon variation in oxygen concentration and contributes to optimal metabolic adaptation to oxygen variations.

A novel adenylate isopentenyltransferase 5 regulates shoot branching via the ATTTA motif in Camellia sinensis

“…The regulatory effects of ATTTA motif and other ARE during different developmental stages or under environmental stimui have been frequently reported in higher eukaryotes. For example, optimal metabolic adaptation to oxygen variations relies on ARE-mediated mRNA stability and thus the regulation of gene transcription and enzyme activity in Drosophila cells [ 22 ]. The splice variants of high-glucose-regulated ( HGRG-14 ) mRNA, which contains different numbers of ATTTA motifs, is produced and correlates well with HGRG-14 protein levels under different glucose conditions in human mesangial cells [ 19 ].…”

“…AU-rich elements (AREs) are sequence elements of 50-150 nt that are rich in adenosine and uridine bases and are frequently found in the 3′ UTRs of labile mRNAs [ 15 , 16 ]. In higher eukaryotes, the AUUUA motif, which are among the best-characterized mRNA-destabilizing determinants, and other AREs could decrease gene expression and inhibit mRNA translation (i.e., protein synthesis), at least partially by enhancing the rate of its deadenylation and subsequent mRNA degradation [ 16 – 22 ]. The ATTTA motif was found to be significantly enriched in transcripts with short half-lives in plants [ 20 , 23 , 24 ].…”

“…Mutations in the AUUUA motifs increase mRNA stability and enhance mRNA accumulation [ 17 , 24 ], whereas insertion of AUUUA motifs into a stable mRNA destabilizes the mRNA levels [ 15 , 20 ]. ATTTA and other AREs-specific stability and deadenylation of mRNA appear to be regulated by development and stress [ 17 , 20 – 22 ]. In Arabidopsis , modulation of mRNA stability contributes to the clock-regulated expression of AtGUTs which contain AUUUA motifs [ 25 ].…”

Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells

“…In addition, vitamin C prevented mRNA decay, as the inhibition of antioxidant responsive element (ARE)-mediated decay of mRNA was among the top three pathways to be upregulated after vitamin C treatment (Figure 2A). This pathway has been documented to play a major role in regulating inflammation [22,23]. Furthermore, vitamin C upregulated both the BAG-2 and ubiquitination pathways.…”

Drosophila cap-binding protein eiF4EHP promotes translation via a 3’UTR-dependent mechanism under hypoxia and contributes to fruit fly adaptation to oxygen variations

“…Both Drosophila larvae and adult flies as well as Drosophila S2 cells were shown to be highly resistant to low O 2 concentrations, making this model organism very attractive to study hypoxic translation 18,19 . We previously identified Ldh encoding lactate dehydrogenase as a highly regulated gene upon oxygen variations in S2 cells 19 . In the present study, we characterized the mechanism promoting translation of Ldh mRNA under hypoxic conditions in Drosophila .…”