AT-1 is the ER membrane acetyl-CoA transporter and is essential for cell viability

Abstract

SummaryThe transient or permanent modification of nascent proteins in the early secretory pathway is an essential cellular function that ensures correct folding and maturation of membrane and secreted proteins. We have recently described a new form of post-translational regulation of the membrane protein b-site APP cleaving enzyme 1 (BACE1) involving transient lysine acetylation in the lumen of the endoplasmic reticulum (ER). The essential components of this process are two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 and ATase2, and a membrane transporter that translocates acetyl-CoA into the lumen of the ER. Here, we report the functional identification of acetyl-CoA transporter 1 (AT-1) as the ER membrane acetyl-CoA transporter. We show that AT-1 regulates the acetylation status of ER-transiting proteins, including the membrane proteins BACE1, low-density lipoprotein receptor and amyloid precursor protein (APP). Finally, we show that AT-1 is essential for cell viability as its downregulation results in widespread cell death and induction of features characteristic of autophagy.

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

“…We previously reported that the influx of acetyl‐CoA from the cytosol to the ER lumen by AT‐1 regulates the induction of ER‐autophagy and the disposal of protein aggregates within the secretory pathway (Jonas et al, 2010; Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014 ). Therefore, it is possible that a defect in ER‐autophagy (also referred to as reticulophagy) is at the basis of the progeria‐like phenotype of AT‐1 sTg mice.…”

“…Therefore, the model may provide insights into a range of age‐related diseases and conditions, and studies on ATase1/ATase2 inhibitors might be relevant for chronic diseases linked to proteostatic dysfunction. For example, the entire ER acetylation machinery, AT‐1 (Gomez Ravetti, Rosso, Berretta, & Moscato, 2010; Jonas et al, 2010) and the ATases (Ding et al, 2012), is upregulated in patients with late‐onset Alzheimer's disease, the most common form of age‐associated dementia. Importantly, both haploinsufficiency of AT‐1 and biochemical inhibition of the ATases using compound 9 were able to rescue the Alzheimer's disease‐like phenotype in the mouse (Duran‐Aniotz, Cornejo, & Hetz, 2016; Peng et al, 2016).…”

“…Real‐time PCR was performed as described before (Jonas et al, 2010). Further details are in Supporting Information.…”

“…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.…”

“…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).…”