TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex.
TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex.
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DOI：
10.1038/s41467-023-44229-4
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发表时间：
2024-01-09
影响因子：
16.6
通讯作者：
Henske, Elizabeth P.
中科院分区：
文献类型：
--
作者：
Alesi, Nicola;Khabibullin, Damir;Rosenthal, Dean M.;Akl, Elie W.;Cory, Pieter M.;Alchoueiry, Michel;Salem, Samer;Daou, Melissa;Gibbons, William F.;Chen, Jennifer A.;Zhang, Long;Filippakis, Harilaos;Graciotti, Laura;Miceli, Caterina;Monfregola, Jlenia;Vilardo, Claudia;Morroni, Manrico;Di Malta, Chiara;Napolitano, Gennaro;Ballabio, Andrea;Henske, Elizabeth P.
多发性硬化症（TSC）是由TSC 1或TSC 2突变引起的，导致雷帕霉素复合物1（mTORC 1）的机制靶点过度活化，以及包括肺（淋巴管平滑肌瘤病）和肾（血管平滑肌脂肪瘤和肾细胞癌）在内的多个器官的病变。以前，我们发现TFEB在TSC中具有组成性活性。在这里，我们产生了两个TSC小鼠模型，其中肾脏病理是主要表型。TFEB的敲除挽救了肾脏病理学和总生存期，表明TFEB是TSC中肾脏疾病的主要驱动因素。重要的是，TSC 2敲除肾脏中增加的mTORC 1活性通过TFEB敲除而正常化。在TSC 2缺陷细胞中，Rheb敲除或雷帕霉素处理矛盾地增加了mTORC 1位点的TFEB磷酸化，并将TFEB从细胞核重新定位到细胞质。在小鼠中，雷帕霉素治疗使溶酶体基因表达正常化，类似于TFEB敲除，表明雷帕霉素在TSC中的益处是TFEB依赖性的。这些结果改变了TSC中mTORC 1过度激活机制的观点，并可能导致治疗途径。多发性硬化症（TSC）是由TSC 1或TSC 2突变引起的，导致雷帕霉素复合物1（mTORC 1）的机制靶点过度活化和多器官肿瘤。在这里，作者表明TFEB是TSC中肾脏疾病和mTORC 1过度激活的主要驱动因素。
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. Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs. Here, the authors show that TFEB is the primary driver of renal disease and mTORC1 hyperactivation in TSC.
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影响因子：
16.6
作者：
Liu, Heng-Jia;Du, Heng;Khabibullin, Damir;Zarei, Mahsa;Wei, Kevin;Freeman, Gordon J.;Kwiatkowski, David J.;Henske, Elizabeth P.
通讯作者：
Henske, Elizabeth P.
影响因子：
11.1
作者：
Di Malta, Chiara;Zampelli, Angela;Granieri, Letizia;Vilardo, Claudia;De Cegli, Rossella;Cinque, Laura;Nusco, Edoardo;Pece, Salvatore;Tosoni, Daniela;Sanguedolce, Francesca;Sorrentino, Nicolina Cristina;Merino, Maria J.;Nielsen, Deborah;Srinivasan, Ramaprasad;Ball, Mark W.;Ricketts, Christopher J.;Vocke, Cathy D.;Lang, Martin;Karim, Baktiar;Lanfrancone, Luisa;Schmidt, Laura S.;Linehan, W. Marston;Ballabio, Andrea
通讯作者：
Ballabio, Andrea
影响因子：
81.5
作者：
Henske, Elizabeth P.;Jozwiak, Sergiusz;Thiele, Elizabeth A.
通讯作者：
Thiele, Elizabeth A.
影响因子：
9.2
作者：
Long, X;Lin, Y;Avruch, J
通讯作者：
Avruch, J
影响因子：
168.9
作者：
Bissler, John J.;Kingswood, J. Christopher;Budde, Klemens
通讯作者：
Budde, Klemens