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RNA deadenylation by CCR4–NOT controls heart function

Nature Reviews Cardiology volume 15, page 197 (2018)Cite this article

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CCR4–NOT is a well-known mediator of deadenylation — the degradation of the mRNA poly(A) tail — which regulates gene expression by inducing mRNA degradation and reducing the quantity of translatable mRNA. The link between the deadenylase activity of CCR4–NOT and the role of this complex in heart function had never before been established. Analysis of knockout mice with cardiac muscle-specific deletion of the Cnot1 or Cnot3 subunits of CCR4–NOT showed that the loss of CCR4–NOT results in severe cardiac contractility defects and arrhythmic changes. Knockout of Cnot3 in cardiomyocytes was also accompanied by an increase in several autophagy proteins, including Atg7, and in cell death. RNA immunoprecipitation of heart lysates using Cnot3 antibody followed by high-throughput RNA sequencing confirmed the interaction of Atg7 with CCR4–NOT and identified transcription and epigenetic factors as additional targets of the deadenylation complex. Simultaneous knockout of Atg7 and Cnot1 or Cnot3 rescued the cardiac defects observed in the single Cnot1 or Cnot3-knockout animals. Additionally, siRNA-mediated depletion of Cnot3 in cardiomyocytes increased the nuclear translocation of Atg7 and p53 and induced the expression of cell death-associated genes. These findings implicate “a new mode of autophagy-associated cell death,” explains lead investigator of the study, Keiji Kuba.

These findings implicate a new mode of autophagy-associated cell death

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References

  1. Yamaguchi, T. et al. The CCR4–NOT deadenylase complex controls Atg7-dependent cell death and heart function. Sci. Signal. 11, eaan3638 (2018)

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  1. Alexandra Le Bras
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Delbridge, L. M. D. et al. Myocardial stress and autophagy: mechanisms and potential therapies. Nat. Rev. Cardiol. 14, 412–415 (2017)

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Le Bras, A. RNA deadenylation by CCR4–NOT controls heart function. Nat Rev Cardiol 15, 197 (2018). https://doi.org/10.1038/nrcardio.2018.14

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  • DOI: https://doi.org/10.1038/nrcardio.2018.14

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