Dithiothreitol causes toxicity in C. elegans by modulating the methionine-homocysteine cycle

Mapping Intimacies ◽

10.1101/2021.11.16.468906 ◽

2021 ◽

Author(s):

Gokul G ◽

Jogender Singh

Keyword(s):

Dependent Manner ◽

Loss Of Function ◽

Genetic Studies ◽

Cellular Physiology ◽

C Elegans ◽

Unfolded Protein ◽

Oxidative Protein Folding ◽

Dietary Component ◽

Protein Response ◽

Redox Reagent

The redox reagent dithiothreitol (DTT) causes stress in the endoplasmic reticulum (ER) by disrupting its oxidative protein folding environment, which results in the accumulation and misfolding of the newly synthesized proteins. DTT may potentially impact cellular physiology by ER-independent mechanisms; however, such mechanisms remain poorly characterized. Using the nematode model Caenorhabditis elegans, here we show that DTT toxicity is modulated by the bacterial diet. Specifically, the dietary component vitamin B12 alleviates DTT toxicity in a methionine synthase-dependent manner. Using a forward genetic screen, we identify that loss-of-function of R08E5.3, an S-adenosylmethionine (SAM)-dependent methyltransferase, imparts resistance to DTT. DTT upregulates R08E5.3 expression and modulates the activity of the methionine-homocysteine cycle. Employing genetic studies, we show that DTT toxicity is a result of the depletion of SAM. Finally, we show that a functional IRE-1/XBP-1 unfolded protein response pathway is required to counteract toxicity at high, but not low, DTT concentrations.

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Mitochondrial UPR negatively regulates wounding-induced innate immune response in C. elegans epidermis

10.1101/2021.09.19.460990 ◽

2021 ◽

Author(s):

Jianzhi Zhao ◽

Hongying Fu ◽

Hengda Zhou ◽

Xuecong Ren ◽

Yuanyuan Wang ◽

...

Keyword(s):

Immune Response ◽

Signaling Pathways ◽

Innate Immune Response ◽

Tissue Damage ◽

P38 Map Kinase ◽

Innate Immune ◽

Loss Of Function ◽

C Elegans ◽

Unfolded Protein ◽

Protein Response

Tissue damage elicits a rapid innate immune response that is essential for efficient wound healing and survival of metazoans. It is well known that p38 MAPK kinase, TGF-β, and hemidesmosome signaling pathways have been involved in wounding-induced innate immunity in C. elegans. Here, we find that loss of function of ATFS-1 increased innate immune response while an elevated level of mitochondrial unfolded protein response (mitoUPR) inhibits the innate immune response upon epidermal wounding. Epidermal wounding triggers the nucleus export of ATFS-1 and inhibits themitoUPR in C. elegans epidermis. Moreover, genetic analysis suggests that ATFS-1 functions upstream of the p38 MAP kinase, TGF-β, and DAF-16 signaling pathways in regulating AMPs induction. Thus, our results suggest that the mitoUPR function as an intracellular signal required to fine-tune innate immune response after tissue damage.

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Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

Communications Biology ◽

10.1038/s42003-021-02218-7 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Priyanka Joshi ◽

Michele Perni ◽

Ryan Limbocker ◽

Benedetta Mannini ◽

Sam Casford ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Unfolded Protein Response ◽

Neurodegenerative Disorders ◽

C Elegans ◽

Unfolded Protein ◽

Model Of Alzheimer’S Disease ◽

Age Related ◽

Parkinson’S Diseases ◽

Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

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A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽

10.1093/genetics/162.4.1631 ◽

2002 ◽

Vol 162 (4) ◽

pp. 1631-1639

Author(s):

Yo Suzuki ◽

Gail A Morris ◽

Min Han ◽

William B Wood

Keyword(s):

Caenorhabditis Elegans ◽

Body Shape ◽

Small Body ◽

Dependent Manner ◽

Loss Of Function ◽

Cellular Mechanisms ◽

C Elegans ◽

Gene Expression Analyses ◽

Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

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H3K27 modifiers regulate lifespan in C. elegans in a context-dependent manner

BMC Biology ◽

10.1186/s12915-021-00984-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Abigail R. R. Guillermo ◽

Karolina Chocian ◽

Gavriil Gavriilidis ◽

Julien Vandamme ◽

Anna Elisabetta Salcini ◽

...

Keyword(s):

Lifespan Extension ◽

Dependent Manner ◽

Loss Of Function ◽

Animal Cells ◽

C Elegans ◽

Specific Effects ◽

Aberrant Gene Expression ◽

Lysine Methyltransferase ◽

Epigenetic Signatures ◽

Aberrant Gene

Abstract Background Evidence of global heterochromatin decay and aberrant gene expression in models of physiological and premature ageing have long supported the “heterochromatin loss theory of ageing”, which proposes that ageing is aetiologically linked to, and accompanied by, a progressive, generalised loss of repressive epigenetic signatures. However, the remarkable plasticity of chromatin conformation suggests that the re-establishment of such marks could potentially revert the transcriptomic architecture of animal cells to a “younger” state, promoting longevity and healthspan. To expand our understanding of the ageing process and its connection to chromatin biology, we screened an RNAi library of chromatin-associated factors for increased longevity phenotypes. Results We identified the lysine demethylases jmjd-3.2 and utx-1, as well as the lysine methyltransferase mes-2 as regulators of both lifespan and healthspan in C. elegans. Strikingly, we found that both overexpression and loss of function of jmjd-3.2 and utx-1 are all associated with enhanced longevity. Furthermore, we showed that the catalytic activity of UTX-1, but not JMJD-3.2, is critical for lifespan extension in the context of overexpression. In attempting to reconcile the improved longevity associated with both loss and gain of function of utx-1, we investigated the alternative lifespan pathways and tissue specificity of longevity outcomes. We demonstrated that lifespan extension caused by loss of utx-1 function is daf-16 dependent, while overexpression effects are partially independent of daf-16. In addition, lifespan extension was observed when utx-1 was knocked down or overexpressed in neurons and intestine, whereas in the epidermis, only knockdown of utx-1 conferred improved longevity. Conclusions We show that the regulation of longevity by chromatin modifiers can be the result of the interaction between distinct factors, such as the level and tissue of expression. Overall, we suggest that the heterochromatin loss model of ageing may be too simplistic an explanation of organismal ageing when molecular and tissue-specific effects are taken into account.

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Small Molecule Stabilization of PINK-1/PINK1 Improves Neurodegenerative Disease

10.1101/2021.06.07.447442 ◽

2021 ◽

Author(s):

Elissa Tjahjono ◽

Jingqi Pei ◽

Alexey V Revtovich ◽

Terri-Jeanne E Liu ◽

Alisha Swadi ◽

...

Keyword(s):

Neurodegenerative Disease ◽

Dependent Manner ◽

Loss Of Function ◽

Mitochondrial Fragmentation ◽

Atp Production ◽

C Elegans ◽

Mitochondrial Homeostasis ◽

Phenotypic Screen ◽

Gfp Reporter ◽

Common Causes

Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of two regulators of mitophagy, PINK1 and Parkin, are amongst the most common causes of recessive Parkinson's disease. Activation of mitophagy via pharmacological treatments may be a feasible approach for combating neurodegeneration. In this effort, we screened ~45,000 small molecules for the ability to activate mitophagy. A high-throughput, whole-organism, phenotypic screen was conducted by monitoring stabilization of PINK-1/PINK1, a key event in mitophagy activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that induced mitophagy, as evidenced by increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes (including delayed paralysis in a C. elegans Alzheimer's model) in a PINK-1/PINK1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.

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HSP-4/BiP expression in secretory cells is regulated by a lineage-dependent differentiation program and not by the unfolded protein response

10.1101/388272 ◽

2018 ◽

Author(s):

Ji Zha ◽

Jasmine Alexander-Floyd ◽

Tali Gidalevitz

Keyword(s):

Unfolded Protein Response ◽

Secretory Cells ◽

C Elegans ◽

Unfolded Protein ◽

Daughter Cells ◽

Developmental Program ◽

The Unfolded Protein Response ◽

Stress Dependent ◽

Protein Response ◽

Anticipatory Activation

AbstractDifferentiation of secretory cells leads to sharp increases in protein synthesis, challenging ER proteostasis. Anticipatory activation of the unfolded protein response (UPR) prepares cells for the onset of secretory function by expanding the ER size and folding capacity. How cells ensure that the repertoire of induced chaperones matches their post-differentiation folding needs is not well understood. We find that during differentiation of stem-like seam cells, a typical UPR target, the C. elegans BiP homologue HSP-4, is selectively induced in alae-secreting daughter cells, but is repressed in hypodermal daughter cells. Surprisingly, this lineage-dependent induction bypasses the requirement for UPR signaling, and instead is controlled by a specific developmental program. The repression of HSP-4 in hypodermal-fated cells requires a transcriptional regulator BLMP-1/BLIMP1, involved in differentiation of mammalian secretory cells. The HSP-4 induction is anticipatory, and is required for the integrity of secreted alae. Thus, differentiation programs can directly control a broad-specificity chaperone that is normally stress-dependent, to ensure the integrity of secreted proteins.

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Abstract 3760: Atherogenic Affects Of Arsenic: Role Of Endoplasmic Reticulum Stress And Unfolded Protein Response

Circulation ◽

10.1161/circ.118.suppl_18.s_482 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Petra Haberzettl ◽

Elena Vladykovskaya ◽

Oleg Barski ◽

Srinivas Sithu ◽

Stanley D’Souza ◽

...

Keyword(s):

Transcription Factor ◽

Unfolded Protein Response ◽

Atherosclerotic Lesion ◽

The United States ◽

Hazardous Substance ◽

Dependent Manner ◽

Lesion Formation ◽

Chemical Chaperone ◽

Unfolded Protein ◽

Protein Response

Arsenic is a global water contaminant and EPA has listed arsenic as a high priority hazardous substance in the United States. Epidemiological studies suggest that chronic arsenic ingestion increases cardiovascular disease in humans, particularly, carotid atherosclerosis. However, mechanisms of arsenic-induced atherogenesis are unknown. We examined the effect of arsenic exposure on early lesion formation in apoE-null mice maintained on water supplemented with (0, 1, 5 and 50 ppm; 3–16 weeks of age) sodium arsenite. Arsenic, did not affect plasma cholesterol but decreased the triglycerides by 18±4 % (P<0.05). NMR analysis of the lipoproteins showed a significant decrease in the abundance of large VLDL particle (>60 nm diameter). Despite a significant decrease in plasma triglyceride, atherosclerotic lesion formation was significantly increased (2– 4 fold; P<0.05 for all doses) in the aortic sinus and the aortic arch of the arsenic-fed mice in a dose dependent manner. Immunohistochemical analysis showed significant increase in the accumulation of macrophages, expression of MCP-1 and unfolded protein response (UPR) dependent activating transcription factor (ATF)-4 and ATF3, in the lesions of arsenic (1ppm) exposed mice. In vitro , arsenic (5–25 μM), significantly increased the expression of ICAM-1, transmigration of differentiated monocytes and expression of the pro-inflammatory cytokine IL-8 in vascular endothelial cells (vEC). Arsenic, also increased the expression of ER-chaperones Grp 78, HERP and calnexin (2– 6 fold; P<0.01). Examination of the effect of arsenic on UPR showed that arsenic, induced the splicing of IRE-1 dependent, bZIP transcription factor XBP-1(alarm phase) and increased the phosphorylation of eIF2α (PERK mediated adaptive phase) by 3 fold (P<0.01) in vEC. Arsenic also induced the expression of the downstream effecter proteins of eIF2α-ATF3 (8 fold; P<0.01) and pro-apoptotic protein CHOP (4 fold; P<0.01) in vEC. Chemical chaperone, phenyl butyric acid (PBA), attenuated the arsenic-induced expression of ATF3 (>90%; P<0.001) and CHOP (>90%; P<0.001). These data suggest that ER-stress and UPR could exacerbate arsenic-induced vascular inflammation and promote atherogenesis.

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Phenolic Compounds Reduce the Fat Content in Caenorhabditis elegans by Affecting Lipogenesis, Lipolysis, and Different Stress Responses

Pharmaceuticals ◽

10.3390/ph13110355 ◽

2020 ◽

Vol 13 (11) ◽

pp. 355

Author(s):

Paula Aranaz ◽

David Navarro-Herrera ◽

María Zabala ◽

Ana Romo-Hualde ◽

Miguel López-Yoldi ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Phenolic Compounds ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Lipid Mobilization ◽

C Elegans ◽

Unfolded Protein ◽

Reducing Activity ◽

Protein Response

Supplementation with bioactive compounds capable of regulating energy homeostasis is a promising strategy to manage obesity. Here, we have screened the ability of different phenolic compounds (myricetin, kaempferol, naringin, hesperidin, apigenin, luteolin, resveratrol, curcumin, and epicatechin) and phenolic acids (p-coumaric, ellagic, ferulic, gallic, and vanillic acids) regulating C. elegans fat accumulation. Resveratrol exhibited the strongest lipid-reducing activity, which was accompanied by the improvement of lifespan, oxidative stress, and aging, without affecting worm development. Whole-genome expression microarrays demonstrated that resveratrol affected fat mobilization, fatty acid metabolism, and unfolded protein response of the endoplasmic reticulum (UPRER), mimicking the response to calorie restriction. Apigenin induced the oxidative stress response and lipid mobilization, while vanillic acid affected the unfolded-protein response in ER. In summary, our data demonstrates that phenolic compounds exert a lipid-reducing activity in C. elegans through different biological processes and signaling pathways, including those related with lipid mobilization and fatty acid metabolism, oxidative stress, aging, and UPR-ER response. These findings open the door to the possibility of combining them in order to achieve complementary activity against obesity-related disorders.

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Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation

Cells ◽

10.3390/cells9051160 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1160 ◽

Cited By ~ 2

Author(s):

Thoufiqul Alam Riaz ◽

Raghu Patil Junjappa ◽

Mallikarjun Handigund ◽

Jannatul Ferdous ◽

Hyung-Ryong Kim ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Stress Sensor ◽

Cellular Physiology ◽

Unfolded Protein ◽

Therapeutic Benefits ◽

Evolutionarily Conserved ◽

Yin And Yang ◽

Protein Response ◽

Diabetes And Obesity

Inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1α signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1α along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1α function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1α are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.

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