Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase

TLDR

The Sir2 deacetylase modulates organismal lifespan across species, yet the mechanisms by which it extends longevity remain largely unknown. This study investigates whether mammalian SIRT1 regulates cellular stress responses by modulating the FOXO family of transcription factors. The authors demonstrate that oxidative stress induces a SIRT1–FOXO3 complex, with SIRT1 deacetylating FOXO3 both in vitro and in cells. SIRT1 enhances FOXO3‑mediated cell cycle arrest and oxidative stress resistance while suppressing its pro‑apoptotic activity, suggesting Sir2 proteins promote longevity by favoring stress resistance over apoptosis.

Abstract

The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.