The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function

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

アレルギー性気道炎症における性ホルモンおよびリンパ球の役割

Epidemiological data indicate that the prevalence and severity of asthma is higher among females than males after puberty. The influence of sex on asthma incidence suggests that sex hormones could play a role in the pathogenesis of the condition associated with asthma. However, the mechanisms of the affect of sex are not clear. Therefore, in the current study, we investigated the sex differences in allergic inflammation in terms of lymphocyte function, using a murine model of allergic asthma. In either BALB/c or C57BL/6J mice, the airway inflammation in female mice sensitized with OVA followed by OVA inhalation was more severe than that in male mice. The contents of Th2 cytokines, such as IL-4, IL-5 and IL-13, in bronchoalveolar lavage fluid from female mice were significantly increased compared with male mice. The airway inflammation in female mice after adoptive transfer of splenocyte from sensitized female mice was more severe than that in any other combination of donors and recipients. Furthermore, splenocytes from sensitized female mice produced more Th2 cytokines than those from sensitized male mice, upon stimulation with OVA. The degree of airway inflammation induced by lipopolysaccharide inhalation was not significantly different between male and female mice. Our findings suggest that sex differences in allergic airway inflammation are due to those in not only sex hormones but also lymphocytes function