The import of acetyl-CoA into the lumen of the endoplasmic reticulum (ER) by AT‑1/SLC33A1 regulates Nε‑lysine acetylation of ER-cargo proteins and is essential for the efficiency of the secretory pathway. Specifically, it regulates both quality control and autophagy-mediated disposal of protein aggregates (J Cell Sci 2010, 123, 3378; J Biol Chem 2014, 289, 32044; J Biol Chem 2012; 287: 29921; Brain 2016, 139, 937). Mice with reduced ER influx of acetyl‑CoA display excessive induction of autophagy while mice with increased influx display increased efficiency of the secretory pathway. In both cases, lack of homeostatic balance leads to drastic phenotypes (J Neurosci 2014, 34, 6772; J Exp Med 2016, 213,1267). Importantly, a dysfunctional ER-acetylation machinery has been genetically linked to human diseases. To expand upon our findings, we generated three new mouse models: AT-1 sTg, ATase1-/-, and ATase2-/-. AT-1 sTg overexpress AT-1 systemically. They display defective proteostasis within the secretory pathway and a progeria-like phenotype. ATase1-/- and ATase2-/- display increased induction of autophagy with mild inflammatory infiltration of peripheral organs. Here, we will describe the phenotype of the above mice and report novel findings on the molecular mechanisms that regulate protein homeostasis down-stream of the ER acetylation machinery. FINANCIAL SUPPORT: NIH.
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