Differential ER stress as a driver of cell fate following ricin toxin exposure

Peterson-Reynolds, Claire; Mantis, Nicholas J.

doi:10.1096/fba.2021-00005

Cited by 3 publications

(1 citation statement)

References 75 publications

(188 reference statements)

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“…Four stress-related mammalian protein kinases reportedly target the alpha subunit of eIF2: double-stranded RNA-dependent protein kinase R (PKR), RNA-dependent protein kinase-like ER kinase (PERK), eIF2α kinase general control non-repressed 2 (GCN2), and heme-regulated eIF2α kinase (HRI) [1,2]. In particular, eukaryotic ribosomes form a central platform of stress-responsive ISR regulation [3][4][5]. Of note, viral infection-induced double-stranded RNA or xenobiotic-induced 28S rRNA damage facilitates ribosomal binding to dsRNA-binding domains of EIF2AK2 and induces enzymatic activation [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction

Kim,

Jeong,

Ray

et al. 2024

Theranostics

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Rationale: The gut and its accessory organ, the liver, are crucial determinants of metabolic homeostasis via the regulation of circulating lipids for cardiovascular health. In response to environmental insults, cells undergo diverse adaptation or pathophysiological processes via stress-responsive eukaryotic initiation factor 2 alpha (eIF2α) kinase signaling and subsequent cellular reprogramming. We noted that patients with inflammatory gut distress display enhanced levels of ribosomal stress-responsive eIF2α kinase, which is notably associated with lipid metabolic process genes. Based on an assumption that eukaryotic ribosomes are a promising stress-responsive module for molecular reprogramming, chemical ribosome-inactivating stressors (RIS) were assessed for their involvement in enterohepatic lipid regulation. Methods: Experimental assessment was based on prediction using the clinical transcriptome and single-cell RNA-sequencing analysis of inflammatory bowel diseases and obesity. The prediction was verified using RIS exposure models of mice, gut organoids, and intestinal cells. The lipidomic profiling was performed to address RIS-induced intracellular fat alterations. Biochemical processes of the mechanisms were evaluated using RT-PCR, western blot analysis, luciferase reporter assays, and confocal microscopy of genetically ablated or chemically inhibited mice, organoids, and cells. Results: Chemical RIS including deoxynivalenol promoted enterohepatic lipid sequestration while lowering blood LDL cholesterol in normal and diet-induced obese mice. Although ribosomal stress caused extensive alterations in cellular lipids and metabolic genes, the cholesterol import-associated pathway was notably modulated. In particular, ribosomal stress enhanced gut levels of the low-density lipoprotein receptor ( LDLR ) via both transcriptional and post-transcriptional regulation. Subsequently, LDLR facilitated enterohepatic cholesterol accumulation, leading to dyslipidemia in response to ribosomal stress. Moreover, genetic features of stress-responsive LDLR modulators were consistently proven in the inflammation- and obesity-associated gut model. Conclusion: The elucidated ribosome-linked gut lipid regulation provides predictive insights into stress-responsive metabolic rewiring in chronic human diseases as an environmental health prediction.

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Section: Introductionmentioning

confidence: 99%

Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction

Kim,

Jeong,

Ray

et al. 2024

Theranostics

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Induction of the PERK-eIF2α-ATF4 Pathway in M1 Macrophages under Endoplasmic Reticulum Stress

Kolodeeva,

Averinskaya

et al. 2024

Dokl Biochem Biophys

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Translation inhibition can activate two cell death pathways. The first pathway is activated by translational aberrations, the second by endoplasmic reticulum (ER) stress. In this work, the effect of ribosome-inactivating protein type II (RIP-II) viscumin on M1 macrophages derived from the THP-1 cell line was investigated. The number of modified ribosomes was evaluated by real-time PCR. Transcriptome analysis revealed that viscumin induces the ER stress activated by the PERK sensor.

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Durable Immunity to Ricin Toxin Elicited by Intranasally Administered Monoclonal Antibody–Based Immune Complexes

et al. 2022

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Inhalation of ricin toxin (RT) elicits profuse inflammation and cell death within the upper and lower airways, ultimately culminating in acute respiratory distress syndrome. We previously reported that the effects of pulmonary RT exposure in mice are nullified by intranasal administration of an mAb mixture consisting of PB10, directed against ricin’s enzymatic subunit (RTA), and SylH3, directed against ricin’s binding subunit (RTB). We now report that delivery of PB10 and SylH3 as an RT–mAb immune complex (RIC) to mice by the intranasal or i.p. routes stimulates the rapid onset of RT-specific serum IgG that persists for months. RIC administration also induced high-titer, toxin-neutralizing Abs. Moreover, RIC-treated mice were immune to a subsequent 5 × LD50 RT challenge on days 30 or 90. Intranasal RIC administration was more effective than i.p. delivery at rendering mice immune to intranasal RT exposure. Finally, we found that the onset of RT-specific serum IgG following RIC delivery was independent of FcγR engagement, as revealed through FcγR knockout mice and RICs generated with PB10/SylH3 LALA (leucine to alanine) derivatives. In conclusion, a single dose of RICs given intranasally to mice was sufficient to stimulate durable protective immunity to RT by an FcγR-independent pathway.

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Differential ER stress as a driver of cell fate following ricin toxin exposure

Cited by 3 publications

References 75 publications

Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction

Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction

Induction of the PERK-eIF2α-ATF4 Pathway in M1 Macrophages under Endoplasmic Reticulum Stress

Durable Immunity to Ricin Toxin Elicited by Intranasally Administered Monoclonal Antibody–Based Immune Complexes

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