Acetyl-CoA flux from the cytosol to the ER regulates engagement and quality of the secretory pathway

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 po...

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Autores principales: Inca A. Dieterich, Yusi Cui, Megan M. Braun, Alexis J. Lawton, Nicklaus H. Robinson, Jennifer L. Peotter, Qing Yu, Jason C. Casler, Benjamin S. Glick, Anjon Audhya, John M. Denu, Lingjun Li, Luigi Puglielli
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/467b0be5ab394a82a7cfe0300b131b61
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Sumario: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.