Editors' ChoiceTissue Repair

MTORC1-dependent reprogramming

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Science Signaling  03 Nov 2020:
Vol. 13, Issue 656, eabf4729
DOI: 10.1126/scisignal.abf4729

DDIT4 and IFRD1 trigger the inhibition and reactivation of MTORC1 during regenerative repair.

Cells that are damaged or destroyed by injury may be replaced either by the activation of dedicated stem cells or by the reprogramming of mature, differentiated cells. In several organs, repair-associated reprogramming requires the transient inhibition of mechanistic target of rapamycin complex 1 (MTORC1) signaling to stimulate the autophagic degradation of cell type–specific components. This is followed by the reactivation of stem and progenitor gene expression and, later, the resumption of MTORC1 signaling, which stimulates cell proliferation to generate cells that can differentiate to replace the lost cells. The reactivation of MTORC1 signaling is similarly required for metabolically quiescent intestinal and skeletal muscle stem cells to re-enter the cell cycle (see Johnson and Lengner). Miao et al. report that repair driven by transient MTORC1 suppression in the mouse stomach and pancreas required the induction of Ddit4 (DNA damage–induced transcript 4) and Ifrd1 (interferon-related developmental regulator 1). Experiments in mice and organoids showed that DDIT4, which inhibits MTORC1 signaling by activating the MTORC1 negative regulators TSC1 and TSC2, was required for the initial inhibition of MTORC1 signaling after injury and for the induction of autophagic and lysosomal activity associated with dedifferentiation. The maintenance of DDIT4-induced MTORC1 suppression required p53. IFRD1, which has been implicated in lysine deacetylation, was required for the subsequent induction of cellular proliferation through a mechanism that likely involved the degradation of p53. Acetylation protects p53 from degradation, and acetylated p53 accumulated in the absence of IFRD1. Ddit4 and Ifrd1 were also induced during liver and kidney repair in mice, limb regeneration in axolotls, and gut repair in fruit flies, suggesting the conservation of this injury-induced, MTORC1-dependent program for tissue regeneration.

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