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

被引:107
|
作者
Ranek, Mark J. [1 ]
Kokkonen-Simon, Kristen M. [1 ]
Chen, Anna [1 ]
Dunkerly-Eyring, Brittany L. [2 ]
Vera, Miguel Pinilla [1 ]
Oeing, Christian U. [1 ]
Patel, Chirag H. [3 ]
Nakamura, Taishi [1 ]
Zhu, Guangshuo [1 ]
Bedja, Djahida [1 ]
Sasaki, Masayuki [1 ]
Holewinski, Ronald J. [4 ,5 ]
Van Eyk, Jennifer E. [4 ,5 ]
Powell, Jonathan D. [3 ]
Lee, Dong Ik [1 ]
Kass, David A. [1 ,2 ]
机构
[1] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Baltimore, MD 21218 USA
[3] Johns Hopkins Univ, Sch Med, Dept Oncol, Bloomberg Kimmel Inst Canc Immunotherapy,Sidney K, Baltimore, MD 21205 USA
[4] Cedars Sinai Med Ctr, Smidt Heart Inst, Los Angeles, CA 90048 USA
[5] Cedars Sinai Med Ctr, Adv Clin Biosyst Res Inst, Los Angeles, CA 90048 USA
基金
美国国家卫生研究院;
关键词
TUBEROUS SCLEROSIS; PHOSPHORYLATION; INHIBITION; GROWTH; COMPLEX; CGMP; AMPK; ERK;
D O I
10.1038/s41586-019-0895-y
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy(1). Its hyperactivation contributes to disease in numerous organs, including the heart(1,2), 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-3 beta) or stimulates (AKT, ERK and RSK-1) mTORC1 activity(3-9). 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 disease(10-13). 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.
引用
收藏
页码:264 / +
页数:25
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