Amino Acid Biosynthesis Regulation during Endoplasmic Reticulum Stress Is Coupled to Protein Expression Demands

Gonen, Nir; Meller, Anatoly; Sabath, Niv; Shalgi, Reut

doi:10.1016/j.isci.2019.07.022

Cited by 24 publications

(35 citation statements)

References 37 publications

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“…The PERK/CHOP axis, ERO1L, and XBP1 promote the tolerance of cells to the hypoxia microenvironment and alter the metabolism function of mitochondria. [21,22,[41][42][43] Consistent with the results of these previous studies, the GO term KEGG pathways associated with hypoxia and metabolism were signi cantly enriched in the preS mutation-induced DEGs identi ed commonly in SB mice and Huh7 cells. The preS mutation-activated ER stress may also promote pro-oncogenic in ammation.…”

Section: Discussionsupporting

confidence: 81%

HBV preS mutations promote hepatocarcinogenesis by inducing endoplasmic reticulum stress and up-regulating inflammatory signaling

Cao

Liu²,

Pu³

et al. 2022

Preprint

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We aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The association between preS mutations and hepatocellular carcinoma (HCC) occurrence was evaluated using a cohort of 2114 HBV-infected patients. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas preS2 deletion significantly increased the HCC risk in patients who received antiviral treatment. The preS1/preS2/S mutants and their wild-type counterpart were delivered into Sleeping Beauty (SB) mouse models. preS1/preS2/S mutants induced a higher tumor rate and higher serum levels of inflammatory cytokines than did wild type-preS1/preS2/S in SB mice. The preS1/preS2/S mutants induced dramatic alteration of gene expression profiles partially through inducing pro-oncogenic inflammatory cytokine. Through enhancing the retention of HBV S protein in endoplasmic reticulum (ER), the preS1/preS2/S mutants enhanced ER stress, induced the alteration in metabolism, affected the response to hypoxia, and upregulated the protein level of signal transducer and activator of transcription 3 (STAT3). Inhibiting the STAT3 pathway attenuated the positive effects of preS1/preS2/S mutants on cell proliferation. Thus, G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism, and pro-oncogenic STAT3 inflammatory pathways, which can be transformed into specific prophylaxis of HCC.

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Section: Discussionsupporting

confidence: 81%

HBV preS mutations promote hepatocarcinogenesis by inducing endoplasmic reticulum stress and up-regulating inflammatory signaling

Cao

Liu²,

Pu³

et al. 2022

Preprint

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“…Finally, pathways such as glycerophospholipid metabolism (strong choline down-regulation) and various amino acid metabolism-related pathways were pinpointed (glutamine and glutamate metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis). Altered amino acid synthesis is related to the fact that the unfolded protein response induces changes in the expression of genes of amino acid transport and synthesis [51].…”

Section: Discussionmentioning

confidence: 99%

Single Spheroid Metabolomics: Optimizing Sample Preparation of Three-Dimensional Multicellular Tumor Spheroids

et al. 2019

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Tumor spheroids are important model systems due to the capability of capturing in vivo tumor complexity. In this work, the experimental design of metabolomics workflows using three-dimensional multicellular tumor spheroid (3D MTS) models is addressed. Non-scaffold based cultures of the HCT116 colon carcinoma cell line delivered highly reproducible MTSs with regard to size and other key parameters (such as protein content and fraction of viable cells) as a prerequisite. Carefully optimizing the multiple steps of sample preparation, the developed procedure enabled us to probe the metabolome of single MTSs (diameter range 790 ± 22 µm) in a highly repeatable manner at a considerable throughput. The final protocol consisted of rapid washing of the spheroids on the cultivation plate, followed by cold methanol extraction. 13C enriched internal standards, added upon extraction, were key to obtaining the excellent analytical figures of merit. Targeted metabolomics provided absolute concentrations with average biological repeatabilities of <20% probing MTSs individually. In a proof of principle study, MTSs were exposed to two metal-based anticancer drugs, oxaliplatin and the investigational anticancer drug KP1339 (sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]), which exhibit distinctly different modes of action. This difference could be recapitulated in individual metabolic shifts observed from replicate single MTSs. Therefore, biological variation among single spheroids can be assessed using the presented analytical strategy, applicable for in-depth anticancer drug metabolite profiling.

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“…In addition to structural differences, we identified alterations of the global transcriptome and metabolome in both MZ and ZZ iHeps, some of which have been previously associated with ER stress or mitochondrial dysfunction (35)(36)(37)42). Among these were enrichment for metabolites significant in the citric acid cycle, glutathione metabolism, and branched chain amino acid and tRNA biosynthesis.…”

Section: Discussionmentioning

confidence: 94%

Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysregulation and Cellular Heterogeneity in PiMZ and PiZZ Hepatocytes

Kaserman

Werder

Wang

et al. 2022

Preprint

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Individuals homozygous for the pathogenic “Z” mutation in alpha-1 antitrypsin deficiency (AATD) are known to be at increased risk for chronic liver disease. That some degree of risk is similarly conferred by the heterozygous state, estimated to affect 2% of the US population, has also become clear. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of expressing a single ZAAT allele on hepatocyte biology. Here, through the application of CRISPR-Cas9 editing, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-derived hepatocytes (iHeps) relative to homozygous mutant (ZZ) or corrected (MM) cells. We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations in hepatic metabolic function including ER and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in subpopulations of cells. Our cellular model of MZ heterozygosity thus provides evidence that expression of a single Z allele is sufficient to disrupt hepatocyte homeostatic function and suggest a mechanism underlying the increased risk of liver disease observed among MZ individuals.

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Amino Acid Biosynthesis Regulation during Endoplasmic Reticulum Stress Is Coupled to Protein Expression Demands

Cited by 24 publications

References 37 publications

HBV preS mutations promote hepatocarcinogenesis by inducing endoplasmic reticulum stress and up-regulating inflammatory signaling

HBV preS mutations promote hepatocarcinogenesis by inducing endoplasmic reticulum stress and up-regulating inflammatory signaling

Single Spheroid Metabolomics: Optimizing Sample Preparation of Three-Dimensional Multicellular Tumor Spheroids

Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysregulation and Cellular Heterogeneity in PiMZ and PiZZ Hepatocytes

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