PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress

Mark J. Ranek, Kristen M. Kokkonen-Simon, Anna Chen, Brittany L. Dunkerly-Eyring, Miguel Pinilla Vera, Christian U. Oeing, Chirag H. Patel, Taishi Nakamura, Guangshuo Zhu, Djahida Bedja, Masayuki Sasaki, Ronald J. Holewinski, Jennifer E. Eyk, Jonathan D. Powell, Dong Ik Lee and David A. Kass ()
Additional contact information
Mark J. Ranek: The Johns Hopkins Medical Institutions
Kristen M. Kokkonen-Simon: The Johns Hopkins Medical Institutions
Anna Chen: The Johns Hopkins Medical Institutions
Brittany L. Dunkerly-Eyring: Johns Hopkins University
Miguel Pinilla Vera: The Johns Hopkins Medical Institutions
Christian U. Oeing: The Johns Hopkins Medical Institutions
Chirag H. Patel: Johns Hopkins University School of Medicine
Taishi Nakamura: The Johns Hopkins Medical Institutions
Guangshuo Zhu: The Johns Hopkins Medical Institutions
Djahida Bedja: The Johns Hopkins Medical Institutions
Masayuki Sasaki: The Johns Hopkins Medical Institutions
Ronald J. Holewinski: Cedars Sinai Medical Center
Jennifer E. Eyk: Cedars Sinai Medical Center
Jonathan D. Powell: Johns Hopkins University School of Medicine
Dong Ik Lee: The Johns Hopkins Medical Institutions
David A. Kass: The Johns Hopkins Medical Institutions

Nature, 2019, vol. 566, issue 7743, 264-269

Abstract: Abstract The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy1. Its hyperactivation contributes to disease in numerous organs, including the heart1,2, although broad inhibition of mTORC1 risks interference with its homeostatic roles. Tuberin (TSC2) is a GTPase-activating protein and prominent intrinsic regulator of mTORC1 that acts through modulation of RHEB (Ras homologue enriched in brain). TSC2 constitutively inhibits mTORC1; however, this activity is modified by phosphorylation from multiple signalling kinases that in turn inhibits (AMPK and GSK-3β) or stimulates (AKT, ERK and RSK-1) mTORC1 activity3–9. Each kinase requires engagement of multiple serines, impeding analysis of their role in vivo. Here we show that phosphorylation or gain- or loss-of-function mutations at either of two adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) can bidirectionally control mTORC1 activity stimulated by growth factors or haemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remains unchanged. In the heart, or in isolated cardiomyocytes or fibroblasts, protein kinase G1 (PKG1) phosphorylates these TSC2 sites. PKG1 is a primary effector of nitric oxide and natriuretic peptide signalling, and protects against heart disease10–13. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knock-in mice that express a phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that cannot be rescued by PKG1 stimulation. However, cardiac disease is reduced and survival of heterozygote Tsc2S1365A knock-in mice subjected to the same stress is improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (TSC2(S1365E)). Resting mTORC1 activity is not altered in either knock-in model. Therefore, TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. The serine residues identified here provide a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.

Date: 2019
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DOI: 10.1038/s41586-019-0895-y

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