Deficient Import of Acetyl-CoA into the ER Lumen Causes Neurodegeneration and Propensity to Infections, Inflammation, and Cancer

Peng, Yi; Li, Mi; Clarkson, Ben; Pehar, Mariana; Lao, Patrick J.; Hillmer, Ansel T.; Barnhart, Todd E.; Christian, Bradley T.; Mitchell, Heather A.; Bendlin, Barbara B.; Sándor, Mátyás; Puglielli, Luigi

doi:10.1523/jneurosci.0077-14.2014

Cited by 51 publications

(128 citation statements)

References 66 publications

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“…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%

“…Acetylation of ER cargo proteins is ensured by three essential elements: AT‐1, ATase1, and ATase2. 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).…”

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%

“…The above disease phenotypes are mimicked by related mouse models. Knock‐in mice that lack AT‐1 activity (AT‐1 S113R/S113R ) die during embryogenesis, while mice with haploinsufficiency of AT‐1 (AT‐1 S113R/+ ) develop neurodegeneration with spasticity and propensity to infections and cancer (Peng et al, 2014). Transgenic mice that overexpress AT‐1 in forebrain neurons (AT‐1 Tg) display an ASD‐like phenotype without dysmorphism (Hullinger et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Transgenic mice that overexpress AT‐1 in forebrain neurons (AT‐1 Tg) display an ASD‐like phenotype without dysmorphism (Hullinger et al, 2016). Mechanistically, the phenotype of AT‐1 S113R/+ mice is linked to aberrant activation of autophagy (Peng et al, 2014) while the phenotype of AT‐1 Tg is linked to increased efficiency of the secretory pathway (Hullinger et al, 2016). When taken together, the convergence of human‐ and mouse‐based studies clearly indicates that the ER acetylation machinery plays fundamental biological functions.…”

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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Identification and Functional Analysis of a SLC33A1: c.339T>G (p.Ser113Arg) Variant in the Original SPG42 Family

Mao

Zhao

et al. 2015

Human Mutation

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Using whole-exome sequencing, we surveyed all the potential pathogenic variants in an SPG42 family and found five SNPs and four indels that are shared by two patients and lie in the mapped region. Two variants, SLC33A1 p.Ser113Arg and VEPH1 p.Gln433His, cosegregated with the disease. However, VEPH1 p.Gln433His was predicted to be tolerated, thus leaving SLC33A1 p.Ser113Arg as the most plausible causal variant in this family. We found that the phosphorylated SMAD1/5/8 (P-SMAD1/5/8) and BMP receptor type 1A (BMPR1A) were substantially upregulated in fibroblasts derived from an SPG42 individual. Slc33a1 knockdown zebrafish, which exhibited defects in morphology and axon outgrowth, also showed a significant elevation in the level of P-smad1/5/8. While the phenotypes in slc33a1 knockdown zebrafish could be rescued by human wild-type SLC33A1 mRNA, this rescuing effect was diminished by coinjected mutant mRNA encoding p.Ser113Arg, indicating that p.Ser113Arg variant acts in a dominant-negative manner. Importantly, pharmacological blockade of BMPR1 activity by dorsomorphin could efficiently rescue the phenotypic defects in slc33a1 knockdown zebrafish. These results indicate that SLC33A1 can negatively regulate BMP signaling.

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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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Deficient Import of Acetyl-CoA into the ER Lumen Causes Neurodegeneration and Propensity to Infections, Inflammation, and Cancer

Cited by 51 publications

References 66 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

Identification and Functional Analysis of a SLC33A1: c.339T>G (p.Ser113Arg) Variant in the Original SPG42 Family

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

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