Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030;
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2977-2986. doi: 10.1073/pnas.1812943116. Epub 2019 Feb 6.
Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.
结节性硬化症复合征（TSC）是一种常染色体显性遗传综合征，可导致多个器官的肿瘤形成。TSC 是由编码 TSC1/2 的基因失活突变引起的，TSC1/2 是哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）的负调节因子。TSC 功能减弱与糖原储存过多有关，但致病机制尚不清楚。通过研究具有缺陷或缺失 TSC2 的人类和小鼠细胞，我们表明 TSC2 的完全缺失会通过 mTORC1 的过度激活和随后的糖原合酶激酶 3β（GSK3β）失活导致糖原合成增加，GSK3β 是糖原合成的负调节因子。然而，特定的 TSC2 致病性突变会导致糖原水平升高，而 mTORC1 或 GSK3β 活性没有变化。我们确定 mTORC1 不依赖的溶酶体耗竭和自噬损伤是 TSC 中异常糖原储存的驱动原因，与潜在突变无关。糖原的自噬降解缺陷与必需的自噬溶酶体途径蛋白的异常泛素化和降解有关，如 LC3 和溶酶体相关膜蛋白 1 和 2（LAMP1/2），并且通过联合使用 mTORC1 和 Akt 药理学抑制剂可以恢复。除了将 mTORC1 作为 TSC 发病机制的核心治疗靶点的当前模型外，我们的发现还确定了 TSC 中失调的 mTORC1 非依赖性途径，因此在开发治疗方法时应考虑这些途径。
