S-acylation-dependent regulation of cytokine receptor signaling and cardiac maladaptation

细胞因子受体信号传导和心脏适应不良的 S-酰化依赖性调节

基本信息

项目摘要

Project Summary Heart disease is the leading cause of death in the United States and worldwide. Mechanisms that spatiotemporally coordinate intracellular signaling in cardiomyocytes remain ill-defined. While the roles of phosphorylation in cardiac signal transduction have been studied for decades, very little is known regarding regulation of signaling by lipid modifications. Cysteine palmitoylation or S-acylation is the reversible attachment of fatty acids onto proteins catalyzed by zDHHC S-acyl transferases. S-acylation is an optimal mechanism to regulate dynamic association of proteins with signaling complexes and receptors at specified membrane domains. Cytokine receptors signal through the Janus kinase (Jak)-Signal transducer and activator of transcription (Stat) pathway to integrate inflammatory and profibrotic signals and mediate inflammatory gene expression programs during cardiac stress, such as the response to pressure overload. In response to pathological stimulation, ischemic injury, or infection, macrophages and other immune cells infiltrate the heart and secrete pro-inflammatory cytokines that activate the Jak-Stat pathway in cardiac myocytes, which when prolonged contributes substantially to adverse cardiac remodeling that hastens disease pathogenesis. Strikingly, unbiased proteomics identified Jak1 as the protein with the most increased S-acylation in hearts of mice with cardiomyocyte-specific overexpression of the Golgi enzyme, zDHHC9. Transgenic mice overexpressing zDHHC9 go on to develop cardiac hypertrophy that progresses to functional decompensation and failure, but this phenotype is preceded by enhanced Jak1 S-acylation and phosphorylation and nuclear translocation of Stat3, suggesting zDHHC9 activates prohypertrophic Jak1/Stat3 signaling in cardiac myocytes in vivo. This proposal will test the central hypothesis that zDHHC9-regulated S- acylation of Jak1 promotes its anterograde trafficking to cytokine receptors, Stat3 activation in response to cytokine stimulation, and consequently maladaptive cardiac remodeling, myocardial inflammation, and heart failure progression. In this application we will manipulate zDHHC9 and Jak1 S-acylation in the context of pressure overload-induced cardiac hypertrophy to achieve the following aims: (1) determine functions of zDHHC9 in the regulation of cardiomyocyte Jak-Stat signaling, hypertrophy and adverse remodeling, and (2) delineate mechanistic roles of Jak1 S-acylation in cytokine receptor signaling during the pathogenesis of cardiac hypertrophy and failure. We will ascertain functions of zDHHC9 and Jak1 S-acylation on Jak1 protein trafficking and stability, Stat3 activation and transcriptional programs, and correlate the kinetics of these signaling outputs with pathophysiologic cardiac inflammation, fibrosis, and cardiomyocyte hypertrophy and apoptosis that promote adverse remodeling and the transition to heart failure. These studies will establish a paradigm for regulated S-acylation as a mechanism governing the duration and amplitude of cardiomyocyte cytokine receptor signaling and identify maladaptive intracellular signaling mechanisms that may provide novel targets for the treatment of heart disease.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Matthew Jacob Brody其他文献

Matthew Jacob Brody的其他文献

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{{ truncateString('Matthew Jacob Brody', 18)}}的其他基金

The role of palmitoylation in cardiac signal transduction and disease pathogenesis
棕榈酰化在心脏信号转导和疾病发病机制中的作用
  • 批准号:
    10213116
  • 财政年份:
    2017
  • 资助金额:
    $ 48.09万
  • 项目类别:
The role of thrombospondin-4 in the secretory pathway, extracellular matrix produ
血小板反应蛋白-4在分泌途径、细胞外基质产物中的作用
  • 批准号:
    9114650
  • 财政年份:
    2014
  • 资助金额:
    $ 48.09万
  • 项目类别:
The role of thrombospondin-4 in the secretory pathway, extracellular matrix produ
血小板反应蛋白-4在分泌途径、细胞外基质产物中的作用
  • 批准号:
    8777607
  • 财政年份:
    2014
  • 资助金额:
    $ 48.09万
  • 项目类别:

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