1. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS
- Author
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Phyllis L. Faust, Rebecca D. Folkerth, Michael B. Kastan, Cheryl L. Walker, Alessia Di Nardo, Durga Nand Tripathi, Angela Alexander, Juliette M. Han, Mustafa Sahin, Andrew R. Tee, Erica Kwiatkowski, Jinhee Kim, Kayleigh M. Dodd, Ruhee Dere, Elaine A. Dunlop, Sheng-Li Cai, Jacqueline Tait-Mulder, and Jiangwei Zhang
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Peroxisome localization ,Gene Expression Regulation, Enzymologic ,Tuberous Sclerosis Complex 1 Protein ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Tuberous Sclerosis Complex 2 Protein ,Autophagy ,Peroxisomes ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,biology ,TOR Serine-Threonine Kinases ,Tumor Suppressor Proteins ,Membrane Proteins ,Cell Biology ,Peroxisome ,Subcellular localization ,Rats ,nervous system diseases ,Cell biology ,HEK293 Cells ,medicine.anatomical_structure ,Multiprotein Complexes ,MCF-7 Cells ,biology.protein ,Cancer research ,TSC1 ,biological phenomena, cell phenomena, and immunity ,TSC2 ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Protein Binding ,Signal Transduction ,RHEB - Abstract
Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by peroxisomal biogenesis factors 19 and 5 (PEX19 and PEX5), respectively, and peroxisome-localized TSC functioned as a Rheb GTPase-activating protein (GAP) to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, and abrogated peroxisome localization, Rheb GAP activity and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS, and peroxisome-localization-deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for the TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signalling organelle involved in regulation of mTORC1.
- Published
- 2013
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