Abstract
mTORC1 inhibits miRNA biogenesis in response to nutrient deprivation by decreasing DROSHA stability.
Major finding: mTORC1 inhibits miRNA biogenesis in response to nutrient deprivation by decreasing DROSHA stability.
Mechanism: mTOR upregulates MDM2, which ubiquitylates DROSHA, targeting it for proteasomal degradation.
Impact: DROSHA-mediated miRNA biogenesis promotes cellular resistance to glucose deprivation.
Development of cancer frequently coincides with loss of miRNA expression, but increased activity of the nutrient sensor mTOR, suggesting a functional link between mTOR signaling and miRNA biogenesis. Ye and colleagues found that deletion of tuberous sclerosis 1 (TSC1), a negative regulator of mTOR activity, resulted in downregulation of miRNA expression and a decrease in precursor miRNA processing, which was reversed with rapamycin treatment, suggesting that mTOR activation inhibits miRNA biogenesis. Consistent with this notion, deletion of the regulatory associated protein of mTOR (Raptor), a component of mTOR complex 1 (mTORC1), resulted in a global increase in miRNAs. In addition, protein levels of DROSHA, which is required for primary miRNA processing, were significantly reduced in Tsc1−/− mouse embryonic fibroblasts, suggesting that mTOR activity modulates miRNA processing via post-transcriptional regulation of DROSHA. In support of this idea, expression of the E3 ubiquitin ligase MDM2 was induced by mTOR activity in both Trp53+/+ and Trp53−/− cells and resulted in decreased DROSHA protein levels due to proteasomal degradation. Recombinant MDM2 was sufficient to ubiquitylate DROSHA in vitro, and depletion of MDM2 in human cells decreased DROSHA ubiquitylation, supporting the hypothesis that mTOR-mediated upregulation of MDM2 directly regulates DROSHA stability. Nutrient availability also affected this signaling pathway, as deprivation of either amino acids or glucose, which reduces mTOR activity, resulted in decreased MDM2 expression and a reciprocal stabilization of DROSHA protein levels and protected glucose-deprived cells from apoptosis. Furthermore, expression of four miRNA mimics identified in a high-throughput screen rescued DROSHA-depleted cells from glucose deprivation, whereas inhibition of these miRNAs sensitized cells to glucose starvation. Together, these data provide evidence for mTOR-mediated regulation of miRNA processing, and suggest that miRNA biogenesis may promote resistance to nutrient deprivation.
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