Harvard Medical School, Boston, MA, 02115, USA.
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
Genome Biol. 2023 Mar 21;24(1):52. doi: 10.1186/s13059-023-02892-2.
Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a phosphorylated peptide (phosphopeptide) is determined by the abundance of its parent protein and the proportion of target sites that are phosphorylated.
We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples of mice from 58 strains of the Collaborative Cross strain panel. We mapped ~700 phosphorylation quantitative trait loci (phQTL) across the three tissues and applied genetic mediation analysis to identify causal drivers of phosphorylation. We identified kinases, phosphatases, cytokines, and other factors, including both known and potentially novel interactions between target proteins and genes that regulate site-specific phosphorylation. Our analysis highlights multiple targets of pyruvate dehydrogenase kinase 1 (PDK1), a regulator of mitochondrial function that shows reduced activity in the NZO/HILtJ mouse, a polygenic model of obesity and type 2 diabetes.
Together, this integrative multi-omics analysis in genetically diverse CC strains provides a powerful tool to identify regulators of protein phosphorylation. The data generated in this study provides a resource for further exploration.
蛋白质磷酸化是调节许多细胞过程的关键步骤，包括酶的激活和信号级联。磷酸肽（磷酸化肽）的丰度取决于其母体蛋白的丰度以及被磷酸化的靶位的比例。
我们定量分析了来自 58 个协作交叉品系面板的小鼠心脏、肝脏和肾脏组织样本中的磷酸肽、蛋白质和转录本。我们在这三种组织中绘制了约 700 个磷酸化数量性状位点（phQTL），并应用遗传中介分析来鉴定磷酸化的因果驱动因素。我们鉴定了激酶、磷酸酶、细胞因子和其他因素，包括目标蛋白和调节特定部位磷酸化的基因之间的已知和潜在的新相互作用。我们的分析强调了丙酮酸脱氢酶激酶 1（PDK1）的多个靶点，PDK1 是一种调节线粒体功能的调节剂，在肥胖和 2 型糖尿病的多基因模型 NZO/HILtJ 小鼠中活性降低。
综上所述，这项在遗传多样化的 CC 品系中进行的综合多组学分析为鉴定蛋白质磷酸化的调节剂提供了一个强大的工具。本研究产生的数据为进一步探索提供了资源。
