Overexpression of ATase1 and ATase2 disrupts the secretome and causes a progeria phenotype.

Nε-lysine acetylation in the lumen of the ER requires two acetyltransferases, ATase1/NAT8B and ATase2/NAT8. They are type II membrane proteins and belong to the larger GNAT superfamily of acetyltransferases. Their enzymatic activity is tightly coupled to the import of acetyl-CoA in the lumen of the ER by AT-1/SLC33A1. Gene duplication events involving 3q25.31 (harboring ) and 2p13.1 (harboring and ) are associated with autism spectrum disorder with intellectual disability and progeria-like dysmorphism. Here, we report the generation and phenotypic characterization of mice with systemic overexpression of ATase1 (ATase1 sTg) and ATase2 (ATase2 sTg). Overexpression of either ATase at conception was found to be lethal while overexpression at birth was found to cause a progeria-like phenotype that included skin alterations, lordokyphosis, reduced bone density, sarcopenia, splenomegaly, adenomegaly, and systemic inflammation. The phenotype of ATase1 sTg mice displayed incomplete penetrance, while the phenotype of ATase2 sTg displayed full penetrance and was more severe. Mechanistically, the phenotype was linked to altered dynamics of the secretory pathway with defects affecting the quality of the secretome.