Fig. 2: Models of REDD1-mediated mTORC1 inhibition and atypical NF-κB activation.

a Schematic showing REDD1-mediated mTORC1 inhibition. Growth factor-activated Akt phosphorylates Ser939 and Ser981 in TSC2 (a GTPase-activating protein, GAP) in the endomembrane-bound TSC1/2 complex (active form), facilitates TSC2/14-3-3 association (inactive GAP) in the cytosol, and inhibits GTP hydrolysis of Rheb, resulting in elevated Rheb-GTP levels and mTORC1 activation. Stress-induced REDD1 sequesters 14-3-3, maintains the active TSC1/2 complexes, hydrolyzes Rheb-GTP, and inhibits mTORC1 activity, thereby decreasing catabolism and increasing anabolism. b Schematic showing REDD1-mediated atypical NF-κB activation. NF-κB activation is generally triggered either by the IKKαβ-dependent canonical pathway or the IKKα-mediated noncanonical pathway following the ligation of cytokine or Toll-like receptors (R) via their cognate ligands (L). Furthermore, REDD1 activates the atypical NF-κB pathway by interacting with and sequestering IκBα, liberating NF-κB p65/50 from IκBα, and translocating it to the nucleus.