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

Farrugia, Mark A.; Puglielli, Luigi

doi:10.1242/jcs.221747

Cited by 39 publications

(51 citation statements)

References 120 publications

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“…Mouse models of altered AT-1 expression are effective models of human AT-1-linked diseases 8–10 . Both cell-based and mouse-based experiments support the conclusion that AT-1 activity regulates ER proteostasis by maintaining the balance between quality control and the induction of reticulophagy 1,2,8–14 .…”

Section: Introductionmentioning

confidence: 73%

“…The acetyl-CoA transporter, AT-1 (also referred to as SLC33A1), is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation 1,2 . Gene duplications in AT-1/SLC33A1 have been identified in patients with autistic-like features, intellectual disability, and dysmorphic features; heterozygous mutations in AT-1/SLC33A1 are associated with a familial form of spastic paraplegia, while homozygous mutations are associated with developmental delay and premature death 3–7 .…”

Section: Introductionmentioning

confidence: 99%

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Acetyl-CoA flux regulates the proteome and acetyl-proteome to maintain intracellular metabolic crosstalk

et al. 2019

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AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation. Dysfunctional ER acetylation, as caused by heterozygous or homozygous mutations as well as gene duplication events of AT-1/SLC33A1 , has been linked to both developmental and degenerative diseases. Here, we investigate two models of AT-1 dysregulation and altered acetyl-CoA flux: AT-1 S113R/+ mice, a model of AT-1 haploinsufficiency, and AT-1 sTg mice, a model of AT-1 overexpression. The animals display distinct metabolic adaptation across intracellular compartments, including reprogramming of lipid metabolism and mitochondria bioenergetics. Mechanistically, the perturbations to AT-1-dependent acetyl-CoA flux result in global and specific changes in both the proteome and the acetyl-proteome (protein acetylation). Collectively, our results suggest that AT-1 acts as an important metabolic regulator that maintains acetyl-CoA homeostasis by promoting functional crosstalk between different intracellular organelles.

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Section: Introductionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Acetyl-CoA flux regulates the proteome and acetyl-proteome to maintain intracellular metabolic crosstalk

et al. 2019

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“…The effect of AT-1 deletion on pancreatic function contributes to a growing understanding of the significance of Nε-lysine acetylation in the ER on protein folding and ER stress responses. [15][16][17] Investigation of the ER acetylome in cultured cell models previously has identified proteins such as glucose-regulated protein 78 (aka BiP Q14…”

Section: Discussionmentioning

confidence: 99%

Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis

Cooley¹,

Thomas²,

Deans³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Pathologic activation of the unfolded protein response is a key event in the development of pancreatitis. Impairing the endoplasmic reticulum acetyl-CoA transporter AT-1 in acini leads to chronic overactivation of the unfolded protein response and presents a spontaneous chronic pancreatitis phenotype. BACKGROUND & AIMS: Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways plays a central role in the development and progression of pancreatitis. Less is known, however, of the consequence of perturbing ER-associated posttranslational protein modifications on pancreatic outcomes. Here, we examined the role of the ER acetyl-CoA transporter AT-1 on pancreatic homeostasis. METHODS: We used an AT-1 S113R/þ hypomorphic mouse model, and generated an inducible, acinar-specific, AT-1 knockout mouse model, and performed histologic and biochemical analyses to probe the effect of AT-1 loss on acinar cell physiology. RESULTS: We found that AT-1 expression is down-regulated significantly during both acute and chronic pancreatitis. Furthermore, acinar-specific deletion of AT-1 in acinar cells induces chronic ER stress marked by activation of both the spliced x-box binding protein 1 and protein kinase R-like ER kinase pathways, leading to spontaneous mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis. Induction of acute-on-chronic pancreatitis in the AT-1 model led to acinar cell loss and glad atrophy. CONCLUSIONS: These results indicate a key role for AT-1 in pancreatic acinar cell homeostasis, the unfolded protein response, and that perturbations in AT-1 function leads to pancreatic disease.

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“…The effect of AT-1 deletion on pancreatic function contributes to a growing understanding of the significance of Nε-lysine acetylation in the ER on protein folding and ER stress responses (18,35,36). Investigation of the ER acetylome in cultured cell models identified proteins such as BiP, LAMP2, and cathepsin D as acetylation targets (37), all of which are critical for pancreatic acinar cell function (38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

“…ER proteostasis is influenced in part by Nε-lysine acetylation of nascent proteins, a posttranslational modification that assists in protein stability and trafficking through the secretory pathway (18). This process is regulated by the ER acetyl-CoA transporter AT-1, which moves cytosolic acetyl-CoA into the ER lumen to be used as a substrate for resident acetyltransferases (19,20).…”

Section: Introductionmentioning

confidence: 99%

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

Ddh

Deans

et al. 2020

Preprint

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Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways play a central role in the development and progression of pancreatitis. A key event in this pathogenic response is a loss of the transcription factor spliced XBP1 (XBP1s) and activation of the PERK pathway. Less is known of the consequence of perturbing ER-associated post-translational protein modification during pancreatitis. Here we show that expression of the ER acetyl-CoA transporter AT-1, necessary for ER protein acetylation, lies downstream of XBP1s and is significantly downregulated during the onset of pancreatitis. Genetic deletion of AT-1 in acinar cells of adult pancreas induces chronic ER stress marked by activation of both the XBP1s and PERK pathways, leading to mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis, but little pancreatic degeneration. Two-day induction of acute on chronic pancreatitis in AT-1 acinar specific knockout mice results in a severe CP phenotype with pronounced pancreatic atrophy. These findings uncover a new layer of complexity of the pathological ER stress response and its impact on pancreatic disease. (189/200) ResultsRelationship of AT-1 expression, ER stress, and pancreatitis. It was previously reported that AT-1 expression is regulated downstream of the IRE1/XBP1s pathway (24). Consistent with this, AT-1 mRNA is significantly downregulated in acinar-specific Ela-Cre XBP1 -/pancreas ( Figure 1A), which display spontaneous pancreatic disease (unpublished results). XBP1s is upregulated in acinar cells during AP as a protective mechanism against ER stress-induced damage, then significantly decreases as the disease progresses (12). Accordingly, AT-1 mRNA is reduced by greater than 50% following cerulein induced AP (CER-AP) in WT mice ( Figure 1B, left), while AT-1 mRNA was decreased in 75% of WT mice subject to CER-CP ( Figure 1B, right). These results suggest that AT-1 loss during pancreatitis is secondary to the reduction in XBP1s activity and, based on the current results, likely exacerbates disease progression.Given the critical role of AT-1 in maintaining ER proteostasis and the well-defined relationship of elevated ER stress and pancreatitis, we examined whether dysregulation of AT-1 function itself would be sufficient to induce pancreatitis. AT-1 S113R/+ mice, which express a hypomorphic mutation that prevents AT-1 dimerization, have an approximate 50% reduction in ER acetyl-CoA transport activity (S113R homozygosity is embryonic lethal) (21).Notwithstanding the immune dysfunction reported in these mice, AT-1 S113R/+ acinar cells display widespread ER dilation and vacuolization, indicative of ER stress and cellular damage, which progresses over time ( Figure 1C). Likewise, AT-1 S113R/+ pancreas have increased collagen deposition ( Figure 1D), a marker of fibrosis.Generation of acinar-specific AT-1 KO ...

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

Cited by 39 publications

References 120 publications

Acetyl-CoA flux regulates the proteome and acetyl-proteome to maintain intracellular metabolic crosstalk

Acetyl-CoA flux regulates the proteome and acetyl-proteome to maintain intracellular metabolic crosstalk

Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis

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

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