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.

缩短和去除mRNA的聚腺苷酸[poly（A）]尾巴，称为腺苷酸化的过程，是通过CCR4-NOT（无TATA的碳分解代谢物阻遏物4阴性）在复合物上介导的mRNA衰减的关键步骤。在我们对心脏中mRNA腺苷酸化调控的研究中，我们发现这种复合物是防止细胞死亡所必需的。CCR4-NOT复合成分Cnot1或Cnot3的有条件删除导致自噬泡的形成和心肌细胞的死亡，导致致命的心力衰竭，伴有较长的QT间隔。Cnot3结合并缩短了编码关键自噬调节剂Atg7的mRNA的poly（A）尾巴。在Cnot3缺失的心脏中，Atg7表达在转录后增加。的遗传消融ATG7，但不是Atg5的，增加存活和的部分恢复心脏功能Cnot1或Cnot3敲除小鼠。我们进一步表明，在Cnot3缺失的心脏中，Atg7与p53相互作用并调节p53活性，从而诱导编码心肌细胞中细胞死亡促进因子的基因表达，表明心脏中腺苷酸化的缺陷异常激活了Atg7和p53从而促进了细胞死亡。 。因此，CCR4-NOT复合物介导的mRNA腺苷酸化对于防止Atg7诱导的细胞死亡和心力衰竭至关重要，这表明mRNA腺苷酸化在靶向自噬基因以维持正常心脏动态平衡方面发挥了作用。