Fig. 2. Caspase-2 controls liver metabolism and ploidy.

a ER-stress can induce the expression of caspase-2 in hepatocytes, which then activates site 1 protease (S1P), localized at the ER, by targeted proteolysis. Active S1P cleaves and activates the SREBP transcription factors (sterol regulatory element-binding protein) that control gene expression programs involved in lipogenesis, and also targets the caspase-2 promoter itself in a feed forward loop. b Upon cytokinesis failure, proliferating hepatocytes in the developing liver engage the PIDDosome for caspase-2 activation to promote p53 induction and p21-dependent cell cycle arrest. Expression of caspase-2 and PIDD1 is under the control of E2F family proteins and thus linked to proliferation. Both PIDDosome components are barely expressed in adult hepatocytes, but are reactivated in an E2F-dependent manner to avoid hyper-polyploidization during liver regeneration.