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A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS

Publication ,  Journal Article
Zhang, J; Kim, J; Alexander, A; Cai, S; Tripathi, DN; Dere, R; Tee, AR; Tait-Mulder, J; Nardo, AD; Han, JM; Kwiatkowski, E; Dunlop, EA ...
Published in: Nature Cell Biology
2013

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. © 2013 Macmillan Publishers Limited. All rights reserved.

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Published In

Nature Cell Biology

DOI

ISSN

1465-7392

Publication Date

2013

Volume

15

Issue

10

Start / End Page

1186 / 1196

Related Subject Headings

  • Developmental Biology
  • 11 Medical and Health Sciences
  • 06 Biological Sciences
 

Citation

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Zhang, J., Kim, J., Alexander, A., Cai, S., Tripathi, D. N., Dere, R., … Walker, C. L. (2013). A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nature Cell Biology, 15(10), 1186–1196. https://doi.org/10.1038/ncb2822
Zhang, J., J. Kim, A. Alexander, S. Cai, D. N. Tripathi, R. Dere, A. R. Tee, et al. “A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS.” Nature Cell Biology 15, no. 10 (2013): 1186–96. https://doi.org/10.1038/ncb2822.
Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nature Cell Biology. 2013;15(10):1186–96.
Zhang, J., et al. “A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS.” Nature Cell Biology, vol. 15, no. 10, 2013, pp. 1186–96. Scival, doi:10.1038/ncb2822.
Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, Tee AR, Tait-Mulder J, Nardo AD, Han JM, Kwiatkowski E, Dunlop EA, Dodd KM, Folkerth RD, Faust PL, Kastan MB, Sahin M, Walker CL. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nature Cell Biology. 2013;15(10):1186–1196.

Published In

Nature Cell Biology

DOI

ISSN

1465-7392

Publication Date

2013

Volume

15

Issue

10

Start / End Page

1186 / 1196

Related Subject Headings

  • Developmental Biology
  • 11 Medical and Health Sciences
  • 06 Biological Sciences