mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation

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Abstract
Cardiomyocytes depend on local translation for growth and can undergo directed growth in length or width in response to different stimuli. Protein synthesis is augmented during concentric hypertrophy, which leads to thickening of the heart muscle by increasing cardiomyocyte width. Protein synthesis is controlled at the translation initiation step, when ribosome loading onto transcripts is regulated by the sequential phosphorylation of the eukaryotic initiation factor 4E–binding protein 1 (4EBP1). Here, we identified a mode of 4EBP1 phosphorylation that was associated with concentric hypertrophy in cultured cardiomyocytes and mouse hearts. Whereas canonical phosphorylation of 4EBP1 by mTORC1 regulates global protein synthesis rates, mTORC1- and nuclear ERK–dependent phosphorylation of 4EBP1 was specifically activated during concentric but not eccentric hypertrophy. Nuclear ERK–dependent phosphorylation of 4EBP1 at Ser 64 was necessary and sufficient to relocalize translation initiation sites closer to the nuclei. ERK activation drove redistribution of ribosomes and nascent translation toward the center of the cardiomyocyte without altering global mRNA distribution, leading to spatially enriched deposition of new sarcomeric protein in the cardiomyocyte interior. Together, these findings demonstrate that global protein synthesis can be spatially regulated by the activation of different kinases in distinct subcellular compartments and identify a mechanism that drives concentric hypertrophy.
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Funding Information
  • National Science Foundation (15-48571)
  • National Science Foundation (15-48571)
  • National Institutes of Health (HL133080)
  • National Institutes of Health (HL149891)
  • National Institutes of Health (T32HL007843)
  • National Institutes of Health (T32 AR053461)
  • National Institutes of Health (F32 HL158027-01)
  • National Institutes of Health (R35HL177035)
  • National Institutes of Health (R01HL128349)
  • American Heart Association (24CDA1267507)
  • United States - Israel Binational Science Foundation (2019126)
  • Fondation Leducq (20CVD01)
  • National Institutes of Health (F31 FHL182030A)
  • United States - Israel Binational Science Foundation (2019126)
  • Fondation Leducq (20CVD01)
  • National Institutes of Health (K08HL159311)
  • Children's Hospital of Philadelphia (Advanced Cardiac Therapies for Heart Failure)

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