Sirtuin 7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4

Sirtuin 7 (SIRT7) is an NAD+-dependent deacetylase/deacylase, but only a limited number of SIRT7 substrates have been identified. Recently, we found that Sirt7 knockout mice are resistant to high-fat diet-induced fatty liver, and that SIRT7 positively regulates the protein level of TR4, a nuclear receptor involved in lipid metabolism, by inhibiting the CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex. However, the mechanism by which SIRT7 inhibits the E3 ubiquitin ligase complex was not identified. Here, we demonstrate that SIRT7 binds directly to DDB1 and deacetylates DDB1 at Lys1121. K1121R-DDB1 (a deacetylation-mimicking mutant) displayed reduced binding with DCAF1. The expression of TR4 protein and TR4 target genes, including Cd36, Cidea, Cidec and Pparg1, was increased in K1121R-DDB1-overexpressing Hepa1-6 cells compared to WT-DDB1-overexpressing cells. Our results indicate that the SIRT7-mediated deacetylation of K1121 attenuates the activity of the CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex by reducing binding between DDB1 and DCAF1, leading to the increased expression of TR4.