State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China.
Tata Institute of Fundamental Research, Hyderabad, India.
Elife. 2024 Oct 22;12:RP88318. doi: 10.7554/eLife.88318.
DYRK1A, a ubiquitously expressed kinase is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the neuromuscular junction as a model, we show that the the fly homologs of , is rescued by RHEB overexpression, suggesting a conserved role of in TORC1 regulation.
DYRK1A 是一种广泛表达的激酶，与人类显性智力发育障碍、小头症和唐氏综合征有关。它调节许多细胞过程，如细胞周期、囊泡运输和微管组装。DYRK1A 是器官生长的关键调节因子；然而，它如何调节器官生长还不完全清楚。在这里，我们表明在哺乳动物细胞中敲低会导致细胞体积减小，这取决于 mTORC1。使用蛋白质组学方法，我们发现 DYRK1A 与结节性硬化复合物 (TSC) 蛋白相互作用，即 TSC1 和 TSC2，它们负调节 mTORC1 的激活。此外，我们表明 DYRK1A 在 TSC2 的 T1462 位点上磷酸化 TSC2，这种修饰已知会抑制 TSC 活性并促进 mTORC1 活性。我们还发现，通过过表达 mTORC1 的激活剂 RHEB，可以挽救 DYRK1A 敲低导致的细胞生长减少。我们的研究结果表明，DYRK1A 通过对 TSC2 的抑制性磷酸化抑制 TSC 复合物的活性，从而促进 mTORC1 的活性。此外，我们使用 神经肌肉接头作为模型，表明 的果蝇同源物 可以通过 RHEB 过表达得到挽救，这表明 在 TORC1 调节中具有保守作用。
