Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Section of Experimental and Technical Sciences, Department of Biomedical Sciences and Public Health, School of Medicine, Università Politecnica delle Marche, Ancona, Italy.
Nat Commun. 2024 Jan 9;15(1):406. doi: 10.1038/s41467-023-44229-4.
Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.
结节性硬化症复合征（TSC）是由 TSC1 或 TSC2 突变引起的，导致雷帕霉素复合物 1（mTORC1）的过度激活和多个器官的病变，包括肺（淋巴管平滑肌瘤病）和肾（血管平滑肌脂肪瘤和肾细胞癌）。先前，我们发现 TSC 中的 TFEB 持续激活。在这里，我们生成了两种 TSC 的小鼠模型，其中肾脏病变是主要表型。TFEB 敲除可挽救肾脏病变和整体存活率，表明 TFEB 是 TSC 肾脏疾病的主要驱动因素。重要的是，TFEB 敲除可使 TSC2 敲除肾脏中的 mTORC1 活性增加正常化。在 TSC2 缺陷细胞中，Rheb 敲低或雷帕霉素处理反常地增加 mTORC1 位点处的 TFEB 磷酸化，并将 TFEB 从核内重新定位到细胞质。在小鼠中，雷帕霉素处理可使溶酶体基因表达正常化，类似于 TFEB 敲除，这表明雷帕霉素在 TSC 中的益处是依赖于 TFEB 的。这些结果改变了 TSC 中 mTORC1 过度激活的机制观点，并可能开辟治疗途径。
