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Acetyl-CoA flux regulates the proteome and acetyl-proteome to maintain intracellular metabolic crosstalk

Inca A. Dieterich, Alexis J. Lawton, Yajing Peng, Qing Yu, Timothy W. Rhoads, Katherine A. Overmyer, Yusi Cui, Eric A. Armstrong, Porsha R. Howell, Maggie S. Burhans, Lingjun Li, John M. Denu, Joshua J. Coon, Rozalyn M. Anderson and Luigi Puglielli ()
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Inca A. Dieterich: University of Wisconsin-Madison
Alexis J. Lawton: University of Wisconsin-Madison
Yajing Peng: University of Wisconsin-Madison
Qing Yu: University of Wisconsin-Madison
Timothy W. Rhoads: University of Wisconsin-Madison
Katherine A. Overmyer: University of Wisconsin-Madison
Yusi Cui: University of Wisconsin-Madison
Eric A. Armstrong: University of Wisconsin-Madison
Porsha R. Howell: University of Wisconsin-Madison
Maggie S. Burhans: University of Wisconsin-Madison
Lingjun Li: University of Wisconsin-Madison
John M. Denu: University of Wisconsin-Madison
Joshua J. Coon: University of Wisconsin-Madison
Rozalyn M. Anderson: University of Wisconsin-Madison
Luigi Puglielli: University of Wisconsin-Madison

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation. Dysfunctional ER acetylation, as caused by heterozygous or homozygous mutations as well as gene duplication events of AT-1/SLC33A1, has been linked to both developmental and degenerative diseases. Here, we investigate two models of AT-1 dysregulation and altered acetyl-CoA flux: AT-1S113R/+ mice, a model of AT-1 haploinsufficiency, and AT-1 sTg mice, a model of AT-1 overexpression. The animals display distinct metabolic adaptation across intracellular compartments, including reprogramming of lipid metabolism and mitochondria bioenergetics. Mechanistically, the perturbations to AT-1-dependent acetyl-CoA flux result in global and specific changes in both the proteome and the acetyl-proteome (protein acetylation). Collectively, our results suggest that AT-1 acts as an important metabolic regulator that maintains acetyl-CoA homeostasis by promoting functional crosstalk between different intracellular organelles.

Date: 2019
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DOI: 10.1038/s41467-019-11945-9

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