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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; Di Nardo, A; Han, JM; Kwiatkowski, E; Dunlop, EA ...
Published in: Nat Cell Biol
October 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.

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Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

October 2013

Volume

15

Issue

10

Start / End Page

1186 / 1196

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 2 Protein
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Reactive Oxygen Species
  • Rats
  • Protein Binding
  • Peroxisomes
  • Multiprotein Complexes
 

Citation

APA
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MLA
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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. Nat Cell Biol, 15(10), 1186–1196. https://doi.org/10.1038/ncb2822
Zhang, Jiangwei, Jinhee Kim, Angela Alexander, Shengli Cai, Durga Nand Tripathi, Ruhee Dere, Andrew R. Tee, et al. “A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS.Nat Cell Biol 15, no. 10 (October 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. Nat Cell Biol. 2013 Oct;15(10):1186–96.
Zhang, Jiangwei, et al. “A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS.Nat Cell Biol, vol. 15, no. 10, Oct. 2013, pp. 1186–96. Pubmed, doi:10.1038/ncb2822.
Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, Tee AR, Tait-Mulder J, Di Nardo A, 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. Nat Cell Biol. 2013 Oct;15(10):1186–1196.

Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

October 2013

Volume

15

Issue

10

Start / End Page

1186 / 1196

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 2 Protein
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Reactive Oxygen Species
  • Rats
  • Protein Binding
  • Peroxisomes
  • Multiprotein Complexes