Abstract

Loss of the tuberous sclerosis complex (TSC) genes TSC1 and TSC2 leads to constitutive activation of the mammalian target of rapamycin complex-1 (mTORC1) and downstream signalling components, resulting in insulin resistance, the development of tumours and neurological disorders. Hotamisligil and colleagues now reveal a previously unrecognized connection between two important, highly conserved pathways — the mTORC1 and the endoplasmic reticulum (ER)-stress pathways — and demonstrate that the ER is wired to the mTOR pathway to control nutrient homeostasis, insulin action and survival.