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.
authors: 1] Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA [2].
authors: Jiangwei
authors: J
authors: Zhang
authors: Jinhee
authors: J
authors: Kim
authors: Angela
authors: A
authors: Alexander
authors: Shengli
authors: S
authors: Cai
authors: Durga Nand
authors: DN
authors: Tripathi
authors: Ruhee
authors: R
authors: Dere
authors: Andrew R
authors: AR
authors: Tee
authors: Jacqueline
authors: J
authors: Tait-Mulder
authors: Alessia
authors: A
authors: Di Nardo
authors: Juliette M
authors: JM
authors: Han
authors: Erica
authors: E
authors: Kwiatkowski
authors: Elaine A
authors: EA
authors: Dunlop
authors: Kayleigh M
authors: KM
authors: Dodd
authors: Rebecca D
authors: RD
authors: Folkerth
authors: Phyllis L
authors: PL
authors: Faust
authors: Michael B
authors: MB
authors: Kastan
authors: Mustafa
authors: M
authors: Sahin
authors: Cheryl Lyn
authors: CL
authors: Walker
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
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