An mTORC1-Mdm2-Drosha Axis for miRNA Biogenesis in Response to Glucose- and Amino Acid-Deprivation

Abstract

mTOR senses nutrient and energy status to regulate cell survival and metabolism in response to environmental changes. Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad reduction in miRNAs due to Drosha degradation. Conversely, targeted mutation of Raptor, an essential component of mTORC 1, increased miRNA biogenesis. mTOR activation increased expression of Mdm2, which is hereby identified as the necessary and sufficient ubiquitin E3 ligase for Drosha. Drosha was induced by nutrient and energy deprivation and conferred resistance to glucose deprivation. Using a high throughput screen of a miRNA library, we identified 4 miRNAs that were necessary and sufficient to protect cells against glucose deprivation-induced apoptosis. These miRNA was regulated by glucose through the mTORC1-MDM2- Drosha axis. Taken together, our data reveal an mTOR-Mdm2-Drosha pathway in mammalian cells that broadly regulates miRNA biogenesis as a response to alteration in cellular environment.

Emerging Role of MicroRNAs in mTOR Signaling

“…For instance, cancer development often associates with increased mTOR activity [23] , but with a loss of many miRNAs targeting this pathway [24] . In particular, mTOR and miRNAs play opposite roles in regulating protein translation and mRNA stability, raising the possibility of close relationship between them [25] (summarized in Figure 2). …”

Micro(RNA) Managing by mTORC1

“…The results by Ye et al (2015) reveal the intricate molecular details involved in this crosstalk by uncovering an mTORC1-Mdm2-Drosha pathway that regulates global miRNA biogenesis. Nutrient-induced mTORC1 activation appears to increase Mdm2 mRNA and protein levels.…”

“… In this issue of Molecular Cell , Ye et al (2015) demonstrate that mTORC1 globally regulates miRNA biogenesis under nutrient-rich conditions via the E3 ubiquitin ligase Mdm2, which promotes Drosha degradation. …”

“…However, the mechanistic link between mTORC1 and miRNA biogenesis was unknown. In this issue, Ye et al (2015) fill in the missing gap by providing evidence that nutrients, such as glucose and amino acids, regulate global miRNAs through mTORC1. Specifically, nutrient-induced mTORC1 activation increases the levels of the E3 ubiquitin ligase Mdm2, which ubiquitinates and targets the miRNA-processing enzyme Drosha for proteasomal-dependent degradation (Figure 1).…”

“…Ye et al (2015) describe a pathway where nutrients regulate global miRNAs through an mTORC1-Mdm2-Drosha signaling cascade. This study reveals how miRNAs may be regulated or sense environmental signals, such as nutrients.…”