Journal
NATURE CELL BIOLOGY
Volume 15, Issue 10, Pages 1186-U145Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncb2822
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Funding
- National Institutes of Health (NIH) [R01 CA143811, NIH R01CA157216, NIH R01N5058956]
- John Merck Fund
- Children's Hospital Boston Translational Research Program
- Association for International Cancer Research Career Development Fellowship [06-914/915]
- Worldwide Cancer Research [06-0914] Funding Source: researchfish
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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.
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