Yang Qian, Li Wenming, She Hua, Dou Juan, Duong Duc M, Du Yuhong, Yang Shao-Hua, Seyfried Nicholas T, Fu Haian, Gao Guodong, Mao Zixu
Department 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.
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Mol Cell. 2015 Feb 19;57(4):721-734. doi: 10.1016/j.molcel.2015.01.004.
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.
微小RNA（miRNA）调控其mRNA靶标的翻译潜能并控制许多细胞过程。经典miRNA生物合成的关键步骤是由核核糖核酸酶III（RNase III）Drosha切割初级转录本。新出现的证据表明，miRNA生物合成级联受到严格控制。然而，对于Drosha是否受到调控却知之甚少。在此，我们表明Drosha是应激的靶点。在应激状态下，p38丝裂原活化蛋白激酶（MAPK）直接在Drosha的N端使其磷酸化。这降低了它与22q11.2微缺失综合征关键区域基因8（DGCR8）的相互作用，并促进其核输出以及被钙蛋白酶降解。这种调控机制介导了应激诱导的Drosha功能抑制。Drosha的减少使细胞对应激敏感并增加死亡。相反，Drosha的增加减轻应激诱导的死亡。这些发现揭示了一种关键的调控机制，即应激通过p38 MAPK途径使Drosha不稳定并抑制Drosha介导的细胞存活。
