Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival
Qian Yang1, Wenming Li2, Hua She2
1Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China; Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract:
MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival.
Insights
Stress destabilizes the microRNA (miRNA) processing enzyme Drosha via p38 MAPK signaling. This mechanism inhibits Drosha function, sensitizing cells to stress and increasing cell death, highlighting a novel stress response pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression, controlling cellular processes through mRNA targeting.
- The biogenesis of miRNAs involves the nuclear enzyme Drosha, but its regulation remains poorly understood.
- Emerging evidence points to tight control over miRNA biogenesis pathways.
Purpose of the Study:
- To investigate the regulation of Drosha, a crucial enzyme in miRNA biogenesis.
- To elucidate the mechanism by which cellular stress affects Drosha function.
- To understand the role of Drosha regulation in cellular stress response and survival.
Main Methods:
- Investigated Drosha regulation under cellular stress conditions.
- Utilized biochemical assays to examine p38 MAPK phosphorylation of Drosha.
- Assessed the impact of Drosha modification on its interaction with DiGeorge syndrome critical region gene 8 (DGCR8).
- Studied nuclear export, degradation pathways (calpain), and cellular sensitivity to stress.
Main Results:
- Cellular stress induces p38 MAPK-mediated phosphorylation of Drosha at its N terminus.
- Phosphorylation reduces Drosha's interaction with DGCR8, promoting nuclear export and calpain-mediated degradation.
- This regulatory mechanism inhibits Drosha activity, leading to reduced miRNA processing.
- Reduced Drosha levels sensitize cells to stress and increase cell death.
- Conversely, increased Drosha levels attenuate stress-induced cell death.
Conclusions:
- Stress triggers a p38 MAPK pathway that destabilizes Drosha, inhibiting its function.
- This pathway represents a critical regulatory mechanism linking cellular stress to miRNA biogenesis and cell survival.
- Drosha regulation is a key determinant of cellular resilience or susceptibility to stress.
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