期刊
CELLS
卷 10, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/cells10102711
关键词
KICSTOR; mTORC1; SZT2; epilepsy; neurogenesis; autophagy; ciliogenesis; neurodegeneration
类别
资金
- Eurac Research (Bolzano, Italy)
- Medical University of Innsbruck
- Eurac Research Institute for Biomedicine by the Department of Innovation, Research, and University of the Autonomous Province of South Tyrol
- Department of Innovation, Research, and University of the Autonomous Province of South Tyrol
- German Tuberous Sclerosis Foundation
- Stichting TSC Fonds
- German Research Foundation [TH 1358/3-1]
- PoLiMeR Innovative Training Network [812616]
- MESI-STRAT project - European Union Horizon 2020 Research and Innovation Program [754688]
- University of Innsbruck [316826]
- Tyrolian Research Fund [18903]
- H2020 Societal Challenges Programme [754688] Funding Source: H2020 Societal Challenges Programme
The study reveals the role of SZT2 in the amino acid-sensing branch of mTORC1, with mutations in this gene causing severe neurodevelopmental and epileptic encephalopathy. Further analysis indicates enhanced mTORC1 signaling activation and higher levels of autophagic components in SZT2 ablated cells.
Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations.
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