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

Abstract

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.

Nε-lysine acetylation in the endoplasmic reticulum – a novel cellular mechanism that regulates proteostasis and autophagy

“…In contrast, large protein aggregates are mostly degraded by the autophagy pathway following encapsulation into autophagosomes and subsequent fusion with the lysosome (Axe et al, 2008;Bernales et al, 2006;Ding et al, 2007;Ogata et al, 2006). As noted earlier, AT-1 S113R/+ mice display hyperactivation of autophagy (Peng et al, 2014), whereas AT-1 sTg mice show hypoactivation, thus supporting an immediate role of the ER acetylation machinery in the regulation of autophagy at the ER level (hence, the term reticulophagy) (Pehar et al, 2012a;Peng et al, 2018). Interestingly, AT-1 is transcriptionally regulated by X-boxbinding-1 protein (XBP-1), which acts immediately downstream of inositol requiring protein-1α (IRE1α; also known as ERN1), one of the three branches of the mammalian unfolded protein response (UPR) system and an upstream initiator of ERAD (Ron and Walter, 2007;Trombetta and Parodi, 2003;Wang and Kaufman, 2016).…”

“…3). Although we still need to resolve the mechanistic aspects of this novel regulatory function, the above hypothesis is supported by recent studies performed in mice with increased or reduced AT-1 activity where ER-to-Golgi trafficking of mature glycoproteins and levels of cell surface proteins were directly measured Peng et al, 2018).…”

“…Further assessment revealed changes in the acetylation status of ER cargo proteins as well as widespread proteomic changes. By contrast, AT-1 sTg mice displayed a segmental progeria phenotype with a maximum lifespan of only ∼5 months that mimicked an accelerated form of pathogenic aging (Peng et al, 2018). The accelerated aging phenotype was accompanied by tissue inflammation and accumulation of senescent cells.…”

“…At the mechanistic level, the reduced AT-1 activity in AT-1 S113R/+ mice resulted in a reduced efficiency of the secretory pathway and hyperactivation of ER autophagy (also referred to as reticulophagy) (Peng et al, 2014). In contrast, overexpression of AT-1 in AT-1 Tg and AT-1 sTg mice resulted in increased efficiency of the secretory pathway and reduced activation of reticulophagy (discussed later) Peng et al, 2018). The fact that homozygous inactivation of AT-1 is lethal and that hemizygous inactivation reduced the import of acetyl-CoA into the ER by ∼50% suggests that AT-1 is the only ER membrane acetyl-CoA transporter (Peng et al, 2014).…”

Deficient ER Acetyl-CoA Import in Acinar Cells Leads to Chronic Pancreatitis

“…In the human population, a S113R mutation in AT-1 manifests as hereditary spastic paraplegias, and AT-1 S113R/+ hypomorphic mice exhibit both neurodegeneration and impaired immune surveillance (21). Chromosomal duplications that include the AT-1 gene are associated with cognitive dysfunction and dysmorphism in humans, and overexpression of AT-1 in mouse models yields a progeria-like phenotype (22,23). These studies underscore the importance of AT-1 activity on protein acetylation and maintenance of ER proteostasis.…”