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.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetyl Coenzyme A / genetics*
  • Acetyl Coenzyme A / metabolism
  • Acetylation
  • Acetyltransferases / genetics*
  • Autophagy / genetics
  • Cytosol / metabolism
  • Endoplasmic Reticulum / genetics*
  • Endoplasmic Reticulum / metabolism
  • Gene Expression Regulation / genetics
  • Golgi Apparatus / genetics
  • Golgi Apparatus / pathology
  • Haploinsufficiency / genetics
  • Humans
  • Lysosomes / genetics
  • Membrane Transport Proteins / genetics*
  • Mutation / genetics
  • Protein Processing, Post-Translational / genetics
  • Protein Transport / genetics
  • Secretory Pathway / genetics


  • Membrane Transport Proteins
  • SLC33A1 protein, human
  • Acetyl Coenzyme A
  • Acetyltransferases