SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation

Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a molecular mechanism that regulates RA signaling and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis. [Display omitted] •CRABPII is a deacetylation substrate of SIRT1•CRABPII K102 acetylation increases its nuclear accumulation and RAR activation•SIRT1 deficiency increases CRABPII acetylation and enhances RA signaling•Loss of SIRT1 accelerates RA-induced mESC differentiation in part through CRABPII Tang et al. show that the most conserved mammalian NAD+-dependent deacetylase SIRT1 affects embryonic stem cell differentiation and embryogenesis by directly modulating acetylation and subcellular localization of cellular retinoic acid binding protein II (CRABPII) to maintain homeostatic retinoic acid signaling.