RIPK1 Promotes Energy Sensing by the mTORC1 Pathway

The mechanisms of cellular energy sensing and AMPK-mediated mTORC1 inhibition are not fully delineated. Here, we discover that RIPK1 promotes mTORC1 inhibition during energetic stress. RIPK1 is involved in mediating the interaction between AMPK and TSC2 and facilitate TSC2 phosphorylation at Ser1387. RIPK1 loss results in a high basal mTORC1 activity that drives defective lysosomes in cells and mice, leading to accumulation of RIPK3 and CASP8 and sensitization to cell death. RIPK1-deficient cells are unable to cope with energetic stress and are vulnerable to low glucose levels and metformin. Inhibition of mTORC1 rescues the lysosomal defects and vulnerability to energetic stress and prolongs the survival of RIPK1-deficient neonatal mice. Thus, RIPK1 plays an important role in the cellular response to low energy levels and mediates AMPK-mTORC1 signaling. These findings shed light on the regulation of mTORC1 during energetic stress and unveil a point of crosstalk between pro-survival and pro-death pathways. [Display omitted] •RIPK1 loss results in elevated mTORC1 activity, causing lysosomal dysfunction•RIPK1 regulates mTORC1 inhibition by AMPK•RIPK1 acts as a scaffold to promote TSC2 phosphorylation by AMPK at Ser1387•mTORC1 inhibitor rapamycin prolongs survival of RIPK1 knockout newborn mice RIPK1 scaffold activity is known to have a pro-survival role in TNFα signaling. Najafov et al. discover an unexpected role for RIPK1 scaffold activity in mediating mTORC1 inhibition by AMPK during energetic stress. Mechanistic studies reveal that RIPK1 is involved in regulating TSC2 phosphorylation at Ser1387 by AMPK. Reduced phosphorylation of this site in RIPK1-deficient cells results in a chronically elevated mTORC1 activity and lysosomal dysfunction.