Editors' ChoiceCell Biology

Inhibiting mTORC1 at the Peroxisome

Sci. Signal.  15 Oct 2013:
Vol. 6, Issue 297, pp. ec250
DOI: 10.1126/scisignal.2004806

Mechanistic target of rapamycin (mTOR) integrates multiple inputs to control cellular anabolic and catabolic processes. Compartmentalized localization of the mTOR complex 1 (mTORC1) and its regulators is one mechanism by which its activity is controlled. Zhang et al. found that the negative mTORC1 regulators TSC1 and TSC2, which form the tuberous sclerosis complex (TSC), and the positive mTORC1 regulator Rheb, a guanosine triphosphatase, colocalized with peroxisomes. Peroxisomes are the main sites of lipid catabolism, a process that produces peroxide, a reactive oxygen species (ROS). The association of TSC2 with peroxisomes was inhibited by expression of a constitutively active form of the kinase Akt, which phosphorylated TSC2, or by exposing the cells to insulin, suggesting a mechanism by which growth factor stimuli regulate the peroxisome-localized pool of mTORC1. TSC2 and the peroxisomal transport protein PEX5 coimmunoprecipitated, and TSC2 had a peroxisomal targeting motif that was sufficient to drive the localization of a fusion protein to peroxisomes. TSC1 coimmunoprecipitated with another peroxisomal membrane protein, PEX19. Rheb is farnesylated, which increases its interaction with endomembranes, and subcellular fractionation analysis showed that a mutant Rheb that could not be farnesylated was not present in the peroxisomal fraction. Naturally occurring mutations in TSC2 were found in the peroxisomal targeting motif, and introduction of these mutations individually into TSC2 compromised peroxisomal localization and coimmunoprecipitation with PEX5. Compared with overexpression of wild-type TSC2, the mutants that could not associate with the peroxisomes did not inhibit mTORC1 activity. Exogenous application of peroxide inhibited mTORC1 activity (based on reduction in the phosphorylation of mTORC1 targets) and increased the abundance of markers of autophagy. Drugs that stimulate the production of peroxisomes also inhibited mTORC1 activity and increased autophagy, whereas cells deficient in peroxisomes from a patient with Zellweger syndrome failed to show TSC2 and Rheb colocalization at peroxisomes and failed to exhibit mTORC1 inhibition in response to peroxide. Thus, the ability to respond to ROS, or at least to peroxide, appears dependent on the association of mTORC1 regulators with peroxisomes, suggesting that ROS regulate this pool of mTORC1 specifically. This contrasts with amino acids, which regulate mTORC1 associated with lysosomes. Benjamin and Hall discuss potential mechanisms for these localized regulatory events and possible communication between mTORC1 at different cellular compartments.

J. Zhang, J. Kim, A. Alexander, S. Cai, D. N. Tripathi, R. Dere, A. R. Tee, J. Tait-Mulder, A. Di Nardo, J. M. Han, E. Kwiatkowski, E. A. Dunlop, K. M. Dodd, R. D. Folkerth, P. L. Faust, M. B. Kastan, M. Sahin, C. L. Walker, A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat. Cell Biol. 15, 1186–1196 (2013). [PubMed]

D. Benjamin, M. N. Hall, TSC on the peroxisome controls mTORC1. Nat. Cell Biol. 15, 1135–1136 (2013). [PubMed]