Abstract:Nε-lysine acetylation in the ER lumen is a recently discovered quality control mechanism that ensures proteostasis within the secretory pathway. The acetyltransferase reaction is carried out by two type-II membrane proteins, ATase1/NAT8B and ATase2/NAT8. Prior studies have shown that reducing ER acetylation can induce reticulophagy, increase ER turnover, and alleviate proteotoxic states. Here, we report the generation of Atase1−/− and Atase2−/− mice and show that these two ER-based acetyltransferases play diff… Show more
“…Finally, treatment was able to restore the Atg9a-Fam134b and Atg9a-Sec62 interaction on the ER (Fig. 2e–g ), which is essential for the proteostatic regulatory functions of the ER acetylation machinery 8 , 10 , 11 . Fig.…”
Section: Resultsmentioning
confidence: 94%
“…This would include patients with AT-1/SLC33A1 duplications as well as normal human aging where increased expression of AT-1 might be disrupting normal proteostasis within the ER and secretory pathway. By studying Atase1 −/− and Atase2 −/− mice, we also discovered that these two acetyltransferases have partially divergent functions with ATase1 playing a more fundamental role in the regulation of reticulophagy 11 . Therefore, compounds that primarily target ATase1 rather than ATase2 are predicted to have stronger translational potential for disease states associated with dysfunctional ER proteostasis.…”
Section: Resultsmentioning
confidence: 96%
“…We previously reported that the acetylation status of ER-bound ATG9A regulates the induction of reticulophagy downstream of the ATases 7 – 11 , 30 . To determine whether the levels of acetylated ATG9A can be useful to monitor target engagement and predict rescue of proteostatic dysfunctions in vivo, we treated AT-1 sTg mice with either Compound 9 or 19 and studied the timeline of the progeria-like phenotype as a function of ATG9A acetylation.…”
Section: Resultsmentioning
confidence: 99%
“…ER acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy (also referred to as reticulophagy or ER-phagy) and the engagement of the secretory pathway 4 – 11 . ER acetylation is ensured by an ER-membrane transporter, AT-1 (also referred to as SLC33A1), that translocates acetyl-CoA from the cytosol to the ER lumen, and two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 (also referred to as NAT8B) and ATase2 (also referred to as NAT8), that acetylate ER cargo proteins within the ER lumen 4 , 12 , 13 .…”
Section: Introductionmentioning
confidence: 99%
“…The ER-bound autophagy protein 9A (ATG9A) is the immediate target for the ATase-mediated regulation of reticulophagy 4 , 7 – 9 , 30 . The acetylation of ATG9A regulates its ability to interact with FAM134B and SEC62, two ER-based autophagy receptors, and engage LC3β and the core autophagy machinery in the cytosol 4 , 8 , 10 , 11 . Importantly, inhibition of ATase1/ATase2 stimulates reticulophagy and helps dispose of toxic protein aggregates that form in the ER lumen/secretory pathway but not in the cytosol 9 .…”
Malfunction of autophagy contributes to the progression of many chronic age-associated diseases. As such, improving normal proteostatic mechanisms is an active target for biomedical research and a key focal area for aging research. Endoplasmic reticulum (ER)-based acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy. ER acetylation is ensured by two ER-membrane bound acetyltransferases, ATase1 and ATase2. Here, we show that ATase inhibitors can rescue ongoing disease manifestations associated with the segmental progeria-like phenotype of AT-1 sTg mice. We also describe a pipeline to reliably identify ATase inhibitors with promising druggability properties. Finally, we show that successful ATase inhibitors can rescue the proteopathy of a mouse model of Alzheimer’s disease. In conclusion, our study proposes that ATase-targeting approaches might offer a translational pathway for many age-associated proteopathies affecting the ER/secretory pathway.
“…Finally, treatment was able to restore the Atg9a-Fam134b and Atg9a-Sec62 interaction on the ER (Fig. 2e–g ), which is essential for the proteostatic regulatory functions of the ER acetylation machinery 8 , 10 , 11 . Fig.…”
Section: Resultsmentioning
confidence: 94%
“…This would include patients with AT-1/SLC33A1 duplications as well as normal human aging where increased expression of AT-1 might be disrupting normal proteostasis within the ER and secretory pathway. By studying Atase1 −/− and Atase2 −/− mice, we also discovered that these two acetyltransferases have partially divergent functions with ATase1 playing a more fundamental role in the regulation of reticulophagy 11 . Therefore, compounds that primarily target ATase1 rather than ATase2 are predicted to have stronger translational potential for disease states associated with dysfunctional ER proteostasis.…”
Section: Resultsmentioning
confidence: 96%
“…We previously reported that the acetylation status of ER-bound ATG9A regulates the induction of reticulophagy downstream of the ATases 7 – 11 , 30 . To determine whether the levels of acetylated ATG9A can be useful to monitor target engagement and predict rescue of proteostatic dysfunctions in vivo, we treated AT-1 sTg mice with either Compound 9 or 19 and studied the timeline of the progeria-like phenotype as a function of ATG9A acetylation.…”
Section: Resultsmentioning
confidence: 99%
“…ER acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy (also referred to as reticulophagy or ER-phagy) and the engagement of the secretory pathway 4 – 11 . ER acetylation is ensured by an ER-membrane transporter, AT-1 (also referred to as SLC33A1), that translocates acetyl-CoA from the cytosol to the ER lumen, and two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 (also referred to as NAT8B) and ATase2 (also referred to as NAT8), that acetylate ER cargo proteins within the ER lumen 4 , 12 , 13 .…”
Section: Introductionmentioning
confidence: 99%
“…The ER-bound autophagy protein 9A (ATG9A) is the immediate target for the ATase-mediated regulation of reticulophagy 4 , 7 – 9 , 30 . The acetylation of ATG9A regulates its ability to interact with FAM134B and SEC62, two ER-based autophagy receptors, and engage LC3β and the core autophagy machinery in the cytosol 4 , 8 , 10 , 11 . Importantly, inhibition of ATase1/ATase2 stimulates reticulophagy and helps dispose of toxic protein aggregates that form in the ER lumen/secretory pathway but not in the cytosol 9 .…”
Malfunction of autophagy contributes to the progression of many chronic age-associated diseases. As such, improving normal proteostatic mechanisms is an active target for biomedical research and a key focal area for aging research. Endoplasmic reticulum (ER)-based acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy. ER acetylation is ensured by two ER-membrane bound acetyltransferases, ATase1 and ATase2. Here, we show that ATase inhibitors can rescue ongoing disease manifestations associated with the segmental progeria-like phenotype of AT-1 sTg mice. We also describe a pipeline to reliably identify ATase inhibitors with promising druggability properties. Finally, we show that successful ATase inhibitors can rescue the proteopathy of a mouse model of Alzheimer’s disease. In conclusion, our study proposes that ATase-targeting approaches might offer a translational pathway for many age-associated proteopathies affecting the ER/secretory pathway.
Huppke–Brendel syndrome (HBS) is an autosomal recessive disorder caused by SLC33A1 mutations, a gene coding for the acetyl‐CoA transporter‐1 (AT‐1). So far it has been described in nine pediatric and one adult patient. Therapeutic trials with copper histidinate failed to achieve any clinical improvement. Here, we describe the clinical characteristics of two novel patients, one of them diagnosed by gene analysis and his sib postmortally based on clinical characteristics. We demonstrate a therapeutic trial with acetylation therapy, consisting of N‐acetylcysteine and ketogenic diet, in one of them. We provide biochemical data on N‐acetylated amino acids in cerebrospinal fluid (CSF) and plasma before and after starting this treatment regimen. Our results indicate that ketogenic diet and N‐acetylcysteine do not seem to normalize the concentrations of N‐acetylated amino acids in CSF or plasma. The overall metabolic pattern shows a trend toward lowered levels of N‐acetylated amino acids in CSF and to a lesser extent in plasma. Although there are some assumptions, the function of AT‐1 is still not clear and further studies are needed to better understand mechanisms underlying this complex disorder.
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