Title: Acetyl‑CoA flux from the cytosol to the ER regulates engagement and quality of the secretory pathway
Legend: Figure. AT-1 sTg and AT-1S113R/+ display a highly heterogeneous cortical secretome. a, b, c, d, Network of significant glycan types plotted to glycoprotein for cortical (a) AT-1 sTg female, (b) AT-1 sTg male, (c) AT-1S113R/+ female, and (d) AT-1S113R/+ male. Circle represents glycan type, with each node representing a specific glycan tree. Glycans intersect with their protein, organized by the number of glycosites identified on that glycoprotein. e, f, g, h, Glycosylation distribution according to subcellular localizations as defined by GO cellular component terms in cortical (e) AT-1 sTg female, (f) AT-1 sTg male, (g) AT-1S113R/+ female, and (h) AT-1S113R/+ male.
Citation: Acetyl-CoA flux from the cytosol to the ER regulates engagement and quality of the secretory pathway. Sci Rep. 2021 Jan 21;11(1):2013. doi: 10.1038/s41598-021-81447-6.(2021).
Abstract: Nε-lysine acetylation in the ER is an essential component of the quality control machinery. ER acetylation is ensured by a membrane transporter, AT-1/SLC33A1, which translocates cytosolic acetyl-CoA into the ER lumen, and two acetyltransferases, ATase1 and ATase2, which acetylate nascent polypeptides within the ER lumen. Dysfunctional AT-1, as caused by gene mutation or duplication events, results in severe disease phenotypes. Here, we used two models of AT-1 dysregulation to investigate dynamics of the secretory pathway: AT-1 sTg, a model of systemic AT-1 overexpression, and AT-1S113R/+, a model of AT-1 haploinsufficiency. The animals displayed reorganization of the ER, ERGIC, and Golgi apparatus. In particular, AT-1 sTg animals displayed a marked delay in Golgi-to-plasma membrane protein trafficking, significant alterations in Golgi-based N-glycan modification, and a marked expansion of the lysosomal network. Collectively our results indicate that AT-1 is essential to maintain proper organization and engagement of the secretory pathway.
About the Lab: The Puglielli Lab’s research interests focus on molecular mechanisms of neurodevelopment and neurodegeneration. The laboratory employs a combination of biochemical, cellular, molecular, and genetic approaches in in vitro, ex vivo and in vivo models.