A Unique ISR Program Determines Cellular Responses to Chronic Stress

Guan, Bo‐Jhih; Hoef, Vincent van; Jobava, Raul; Elroy‐Stein, Orna; Valášek, Leoš Shivaya; Cargnello, Marie; Gao, Xing-Huang; Krokowski, Dawid; Merrick, William C.; Kimball, Scot R.; Komar, Anton A.; Koromilas, Antonis E.; Wynshaw‐Boris, Anthony; Topisirović, Ivan; Larsson, Ola; Hatzoglou, Maria

doi:10.1016/j.molcel.2017.11.007

Cited by 146 publications

(266 citation statements)

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“…While mRNA levels are key determinants of the proteome under non-stressed growth conditions, the contribution of mRNA translation remains contentious (Schwanhäusser et al, 2011;Li et al, 2014Li et al, , 2017. In contrast, it is well established that altered translational efficiencies reshape the proteome during various dynamic responses including cellular differentiation and endoplasmic reticulum stress (Kristensen et al, 2013;Baird et al, 2014;Liu et al, 2016;Guan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer‐associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5′UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome association remains unaltered are enriched in codons requiring U34‐modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34‐modifying enzymes and thereby controls levels of U34‐modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα‐dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone‐dependent cancers.

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Section: Introductionmentioning

confidence: 99%

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

et al. 2019

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“…We previously showed that chronic ER stress in MIN6 cells promotes protein S-sulfhydration which restores stress-induced inhibition of glycolysis (Gao et al, 2015). MIN6 cells were treated with the chemical stressor thapsigargin (Tg) to induce chronic ER stress (Guan et al, 2017). Treatment with Tg induces the ATF4/CTH axis of protein S-sulfhydration (Gao et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Discovery of a redox-thiol switch regulating cellular energy metabolism

Gao

Parisien

et al. 2019

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Previously, we reported that increased synthesis of the gas hydrogen sulfide (H 2 S) during the Integrated Stress Response (ISR) induced proteome-wide cysteine-sulfhydration with the predominant modified pathway being enzymes of cellular energy metabolism (Gao, et al. 2015). Using pancreatic beta cells and quantitative proteomics in this study, we identified a Redox Thiol Switch from Sglutathionylation to S-sulfhydration and we named it, RTS GS . About half of the identified proteins are involved in energy metabolism, and one novel target was the mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) whose catalytic Cys 306 was targeted by both modifications. The enzymatic activity of PCK2 was inhibited by S-glutathionylation, and this inhibition was largely reversed by Ssulfhydration. S-sulfhydration also reversed the S-glutathionylation-mediated inhibition of glucose flux, indicating a broad metabolic significance. We propose that a Redox Thiol Switch from S-glutathionylation to S-sulfhydration is a key mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

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“…The present study demonstrates a marked upregulation and/or dysregulation of pathological cellular pathways including PERK, CHOP, and JNK with loss of AT-1; however, the CP observed in Ela-Cre AT-1 -/appeared to be relatively mild to moderate, suggesting a capability of acinar cells to adapt to chronic ER stress when the UPR is intact. Additionally, a recent study suggests that chronic ER stress induces a switch to eIF3-dependent translation, circumventing eIF2α inhibition and partially restoring protein translation including that of ER functional proteins (30). These compensatory mechanisms allow acini to continue functioning under high stress conditions and may explain, in part, how some cases of CP in humans are asymptomatic (31); indeed, CP manifestation in patients with high alcohol intake varies significantly and, in some cases, is only detected postmortem (32,33).…”

Section: Discussionmentioning

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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A Unique ISR Program Determines Cellular Responses to Chronic Stress

Cited by 146 publications

References 60 publications

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression

Discovery of a redox-thiol switch regulating cellular energy metabolism

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

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