Cheng Tzu-Lin, Wu Feixuan, Haque Md Ezazul, Thiel Abigail R, Wang Danqing, Helgager Jeffrey J, Li Lingjun, Puglielli Luigi
Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
Life Sci Alliance. 2025 Sep 10;8(12). doi: 10.26508/lsa.202503378. Print 2025 Dec.
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.
内质网腔中的Nε-赖氨酸乙酰化需要两种乙酰转移酶，即ATase1/NAT8B和ATase2/NAT8。它们是II型膜蛋白，属于更大的乙酰转移酶GNAT超家族。它们的酶活性与AT-1/SLC33A1将乙酰辅酶A导入内质网腔紧密相关。涉及3q25.31（包含 ）和2p13.1（包含 和 ）的基因复制事件与伴有智力残疾和早衰样畸形的自闭症谱系障碍相关。在此，我们报告了全身性过表达ATase1（ATase1 sTg）和ATase2（ATase2 sTg）的小鼠的产生及表型特征。发现受孕时任何一种ATase的过表达都是致死性的，而出生时过表达则会导致早衰样表型，包括皮肤改变、脊柱后凸、骨密度降低、肌肉减少症、脾肿大、腺肿大和全身炎症。ATase1 sTg小鼠的表型表现为不完全显性，而ATase2 sTg的表型表现为完全显性且更严重。从机制上讲，该表型与分泌途径的动力学改变有关，缺陷影响分泌蛋白质组的质量。
