@article{76023e3b1fd24192a86d698f4aa5bed6,
title = "A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS",
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.",
author = "Jiangwei Zhang and Jinhee Kim and Angela Alexander and Shengli Cai and Tripathi, {Durga Nand} and Ruhee Dere and Tee, {Andrew R.} and Jacqueline Tait-Mulder and {Di Nardo}, Alessia and Han, {Juliette M.} and Erica Kwiatkowski and Dunlop, {Elaine A.} and Dodd, {Kayleigh M.} and Folkerth, {Rebecca D.} and Faust, {Phyllis L.} and Kastan, {Michael B.} and Mustafa Sahin and Walker, {Cheryl Lyn}",
note = "Funding Information: We thank G. Mills and Y. Lu (University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA) for the MCF-7 cell line stably expressing GFP–LC3, and RIKEN BRC for providing the ATG5+/+ MEFs and ATG5−/− MEFs. We are also grateful for the assistance of K. Dunner in electron microscopy image acquisition and analysis and T. Berry, X. Tong and S. Hensley for technical assistance. This work was supported by National Institutes of Health (NIH) Grant R01 CA143811 to C.L.W., NIH R01CA157216 to M.B.K., and NIH R01NS058956, the John Merck Fund, and the Children{\textquoteright}s Hospital Boston Translational Research Program to M.S. A.R.T. was supported by the Association for International Cancer Research Career Development Fellowship (No. 06-914/915).",
year = "2013",
month = oct,
doi = "10.1038/ncb2822",
language = "English (US)",
volume = "15",
pages = "1186--1196",
journal = "Nature cell biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "10",
}