期刊
EMBO REPORTS
卷 22, 期 7, 页码 -出版社
WILEY
DOI: 10.15252/embr.202052173
关键词
lowe syndrome; lysosome positioning; microtubule nucleation; mTOR; OCRL
资金
- NIH/NEI [K08-EY022058, R01-EY025295]
- VA merit [CX001298]
- Ziegler Foundation for the Blind
- Showalter Foundation
- Children's Health Research Institute Award
- Research for Prevention of Blindness Unrestricted grant (Stanford Ophthalmology), American Glaucoma Society
- Lowe syndrome association
- Knights Templar Eye Foundation
- P30 Vision Center grant
- NIH/NEI T32 training grant [T32-EY027816]
- NIH/NEI Kirschstein-NRSA postdoctoral fellowship [F32-EY032775-01]
- NIH [R01-EY-032159, R01-EY-028106, EY031063]
- Glaucoma Research Foundation (CFC3)
- BrightFocus Foundation
- Chan Zuckerberg Initiative Neurodegeneration Collaborative Pairs Pilot Projects
- [R01-EY-023295]
- [R01-EY024932]
This study reveals the crucial role of OCRL in nutrient sensing by showing its localization at the centrosome and recruitment of microtubule-anchoring factor SSX2IP. Deficiency of OCRL leads to loss of microtubule-organizing centers and mTORC1 inactivation, resulting in impaired nutrient sensing. Targeted restoration of microtubule anchoring and mTOR activity can rescue the nutrient sensing ability of cells in Lowe syndrome patients. These findings highlight mTORC1 as a potential therapeutic target for Lowe syndrome.
Lysosomal positioning and mTOR (mammalian target of rapamycin) signaling coordinate cellular responses to nutrient levels. Inadequate nutrient sensing can result in growth delays, a hallmark of Lowe syndrome. OCRL mutations cause Lowe syndrome, but the role of OCRL in nutrient sensing is unknown. Here, we show that OCRL is localized to the centrosome by its ASH domain and that it recruits microtubule-anchoring factor SSX2IP to the centrosome, which is important in the formation of the microtubule-organizing center. Deficiency of OCRL in human and mouse cells results in loss of microtubule-organizing centers and impaired microtubule-based lysosome movement, which in turn leads to mTORC1 inactivation and abnormal nutrient sensing. Centrosome-targeted PACT-SSX2IP can restore microtubule anchoring and mTOR activity. Importantly, boosting the activity of mTORC1 restores the nutrient sensing ability of Lowe patients' cells. Our findings highlight mTORC1 as a novel therapeutic target for Lowe syndrome.
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