The Endoplasmic Reticulum-based Acetyltransferases, ATase1 and ATase2, Associate with the Oligosaccharyltransferase to Acetylate Correctly Folded Polypeptides

Ding, Yun; Dellisanti, Cosma D.; Ko, Mi Hee; Czajkowski, Cynthia; Puglielli, Luigi

doi:10.1074/jbc.m114.585547

Cited by 21 publications

(38 citation statements)

References 38 publications

(61 reference statements)

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“…ATase1 and ATase2 act downstream of AT‐1 to acetylate ER cargo proteins (Ko & Puglielli, 2009), regulate the acetylation status of Atg9a, and are essential for the proteostatic functions of the ER acetylation machinery (Ding et al, 2014; Peng et al, 2016). Our study showed that inhibition of the ATases was able to restore the Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interaction at the ER membrane and rescue the progeria‐like phenotype of AT‐1 sTg mice.…”

Section: Discussionmentioning

confidence: 99%

“…Nε‐lysine acetylation in the lumen of the endoplasmic reticulum (ER) has emerged as a novel mechanism for the regulation of protein homeostasis (also referred to as proteostasis) within the organelle (Ding, Dellisanti, Ko, Czajkowski, & Puglielli, 2014; Hullinger et al, 2016; Jonas, Pehar, & Puglielli, 2010; Pehar, Jonas, Hare, & Puglielli, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014). Acetylation of ER cargo proteins is ensured by three essential elements: AT‐1, ATase1, and ATase2.…”

Section: Introductionmentioning

confidence: 99%

“…AT‐1 (also referred to as SLC33A1) is the ER membrane transporter that regulates the cytosol‐to‐ER flux of acetyl‐CoA, donor of the acetyl group in the reaction of Nε‐lysine acetylation (Jonas et al, 2010; Peng et al, 2014). ATase1 (also referred to as NAT8B) and ATase2 (also referred to as NAT8) are type II ER membrane proteins that carry out the reaction of Nε‐lysine acetylation within the ER lumen (Ding et al, 2014; Ko & Puglielli, 2009). Ex vivo and in vivo data suggest that the ER acetylation machinery is a component of ER quality control and regulates two essential functions of the organelle: (a) selection and transport of cargo proteins along the secretory pathway; and (b) disposal of protein aggregates that form within the ER and secretory pathway (Ding et al, 2014; Hullinger et al, 2016; Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…ATase1 (also referred to as NAT8B) and ATase2 (also referred to as NAT8) are type II ER membrane proteins that carry out the reaction of Nε‐lysine acetylation within the ER lumen (Ding et al, 2014; Ko & Puglielli, 2009). Ex vivo and in vivo data suggest that the ER acetylation machinery is a component of ER quality control and regulates two essential functions of the organelle: (a) selection and transport of cargo proteins along the secretory pathway; and (b) disposal of protein aggregates that form within the ER and secretory pathway (Ding et al, 2014; Hullinger et al, 2016; Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014). The former requires the ATases to associate with the oligosaccharyltransferase complex (OST) and acetylate correctly folded polypeptides (Ding et al, 2014; Peng & Puglielli, 2016) while the latter requires acetylation/deacetylation of the autophagy protein Atg9a (Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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The membrane transporter AT‐1/SLC33A1 translocates cytosolic acetyl‐CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT‐1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT‐1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT‐1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT‐1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl‐CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl‐CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol‐to‐ER flux of acetyl‐CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl‐CoA‐dependent homeostatic mechanisms linked to metabolism and inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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“…Thus, reticular acetyl-CoA levels are expected to increase (at the expense of the nucleo-cytosolic pool) in the course of ER stress responses . In the ER lumen, acetyl-CoA is the substrate of a few acetyltransferases including members of the N-acetyltransferase 8 (NAT8) protein family and calreticulin (CALR, a chaperone with acetyltransferase enzymatic activity) (Ding et al, 2014). Acetylation reactions in the ER lumen may allow correctly folded proteins to progress to the Golgi apparatus for secretion, implying that the reticular pool of acetylCoA could play an important role in protein quality control (Pehar and Puglielli, 2013).…”

Section: Export Of Acetyl-coa From Peroxisomesmentioning

confidence: 99%

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

et al. 2015

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Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger.

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Abnormal concentrations of acetylated amino acids in cerebrospinal fluid in acetyl‐CoA transporter deficiency

Šikić

Peters

Marušić

et al. 2022

J of Inher Metab Disea

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Acetyl-CoA transporter 1 (AT-1) is a transmembrane protein which regulates influx of acetyl-CoA from the cytosol to the lumen of the endoplasmic reticulum and is therefore important for the posttranslational modification of numerous proteins. Pathological variants in the SLC33A1 gene coding for AT-1 have been linked to a disorder called Huppke-Brendel syndrome, which is characterized by congenital cataracts, hearing loss, severe developmental delay and early death. It has been described in eight patients so far, who all had the abovementioned symptoms together with low serum copper and ceruloplasmin concentrations. The link between AT-1 and low ceruloplasmin concentrations is not clear, nor is the complex pathogenesis of the disease. Here we describe a further case of Huppke-Brendel syndrome with a novel and truncating homozygous gene variant and provide novel biochemical data on N-acetylated amino acids in cerebrospinal fluid (CSF) and plasma. Our results indicate that decreased levels of many N-acetylated amino acids in CSF are a typical metabolic fingerprint for AT-1 deficiency and are potential biomarkers for the defect. As acetyl-CoA is an important substrate for protein acetylation, we Katarina Šiki c and Tessa M.A. Peters contributed equally to this study.Ron A. Wevers and Ivo Bari c contributed equally to this study.

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The Endoplasmic Reticulum-based Acetyltransferases, ATase1 and ATase2, Associate with the Oligosaccharyltransferase to Acetylate Correctly Folded Polypeptides

Cited by 21 publications

References 38 publications

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Abnormal concentrations of acetylated amino acids in cerebrospinal fluid in acetyl‐CoA transporter deficiency

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