The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function
The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function
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DOI：
10.1126/scisignal.aan3638
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发表时间：
2018-02-06
影响因子：
7.3
通讯作者：
Kuba, Keiji
中科院分区：
文献类型：
--
作者：
Yamaguchi, Tomokazu;Suzuki, Takashi;Kuba, Keiji
mRNA的聚腺苷酸[poly（A）]尾的缩短和去除（称为去腺苷酸化的过程）是mRNA衰变的关键步骤，其通过CCR 4-NOT（碳分解代谢物阻遏4-阴性TATA-less）复合物介导。在我们对心脏中mRNA去腺苷化调节的研究中，我们发现这种复合物是防止细胞死亡所必需的。CCR 4-NOT复合物组分Cnot 1或Cnot 3的条件性缺失导致自噬空泡的形成和心肌细胞死亡，导致致死性心力衰竭伴随长QT间期。Cnot 3结合并缩短了编码关键自噬调节因子Atg 7的mRNA的poly（A）尾。在Cnot 3缺失的心脏中，Atg 7表达在转录后增加。Atg 7基因切除，而不是Atg 5，增加生存和部分恢复Cnot 1或Cnot 3敲除小鼠的心脏功能。我们进一步表明，在Cnot 3缺失的心脏中，Atg 7与p53相互作用并调节p53活性，以诱导心肌细胞中编码细胞死亡促进因子的基因的表达，表明心脏中去腺苷化的缺陷异常激活Atg 7和p53，以促进细胞死亡。因此，由CCR 4-NOT复合物介导的mRNA去腺苷化对于防止Atg 7诱导的细胞死亡和心力衰竭至关重要，表明mRNA去腺苷化在靶向自噬基因以维持正常心脏稳态中的作用。
Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4-negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4-NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomyocyte death, leading to lethal heart failure accompanied by long QT intervals. Cnot3 bound to and shortened the poly(A) tail of the mRNA encoding the key autophagy regulator Atg7. In Cnot3-depleted hearts, Atg7 expression was posttranscriptionally increased. Genetic ablation of Atg7, but not Atg5, increased survival and partially restored cardiac function of Cnot1 or Cnot3 knockout mice. We further showed that in Cnot3-depleted hearts, Atg7 interacted with p53 and modulated p53 activity to induce the expression of genes encoding cell death-promoting factors in cardiomyocytes, indicating that defects in deadenylation in the heart aberrantly activated Atg7 and p53 to promote cell death. Thus, mRNA deadenylation mediated by the CCR4-NOT complex is crucial to prevent Atg7-induced cell death and heart failure, suggesting a role for mRNA deadenylation in targeting autophagy genes to maintain normal cardiac homeostasis.