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 37 publications

(51 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 1 more Smart Citation

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

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 ...

show abstract

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

Cited by 37 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

Contact Info

Product

Resources

About