Role of Endoplasmic Reticulum ER Stress-Induced Cell Death Mechanisms

Madkour, Loutfy H.

doi:10.1007/978-3-030-37297-2_8

Cited by 2 publications

(1 citation statement)

References 342 publications

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“…Among these compounds, salicylaldehyde-based inhibitors have shown high efficacy by directly blocking the RNase domain ( 25 ). The compounds 4μ8C and STF-083010 are two well-described examples of this class ( 26 – 29 ), but their effects on a fungal pathogen are still unexplored. Here, we demonstrate that 4μ8C ( 30 ) is an inhibitor of the canonical UPR pathway in A. fumigatus , effectively blocking the accumulation of hacA i mRNA and downstream target gene induction.…”

Section: Introductionmentioning

confidence: 99%

A Human IRE1 Inhibitor Blocks the Unfolded Protein Response in the Pathogenic Fungus Aspergillus fumigatus and Suggests Noncanonical Functions within the Pathway

Guirao-Abad

Weichert

Albee

et al. 2020

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The unfolded protein response (UPR) is a signaling network that maintains homeostasis of the endoplasmic reticulum (ER). In the human-pathogenic fungus Aspergillus fumigatus, the UPR is initiated by activation of an endoribonuclease (RNase) domain in the ER transmembrane stress sensor IreA, which splices the downstream mRNA hacAu into its active form, hacAi, encoding the master transcriptional regulator of the pathway. Small-molecule inhibitors against IRE1, the human ortholog of IreA, have been developed for anticancer therapy, but their effects on the fungal UPR are unexplored. Here, we demonstrate that the IRE1 RNase inhibitor 4μ8C prevented A. fumigatus from increasing the levels of hacAi mRNA, thereby blocking induction of downstream UPR target gene expression. Treatment with 4μ8C had minimal effects on growth in minimal medium but severely impaired growth on a collagen substrate that requires high levels of hydrolytic enzyme secretion, mirroring the phenotype of other fungal UPR mutants. 4μ8C also increased sensitivity to carvacrol, a natural compound that disrupts ER integrity in fungi, and hygromycin B, which correlated with reduced expression of glycosylation-related genes. Interestingly, treatment with 4μ8C was unable to induce all of the phenotypes attributed to the loss of the canonical UPR in a ΔhacA mutant but showed remarkable similarity to the phenotype of an RNase-deficient IreA mutant that is also unable to generate the hacAi mRNA. These results establish proof of principle that pharmacological inhibition of the canonical UPR pathway is feasible in A. fumigatus and support a noncanonical role for the hacAu mRNA in ER stress response. IMPORTANCE The unfolded protein response (UPR) is a signaling pathway that maintains endoplasmic reticulum (ER) homeostasis, with functions that overlap virulence mechanisms in the human-pathogenic mold Aspergillus fumigatus. The canonical pathway centers on HacA, its master transcriptional regulator. Translation of this protein requires the removal of an unconventional intron from the cytoplasmic mRNA of the hacA gene, which is achieved by an RNase domain located in the ER-transmembrane stress sensor IreA. Here, we show that targeting this RNase activity with a small-molecule inhibitor effectively blocked UPR activation, resulting in effects that mirror the consequences of genetic deletion of the RNase domain. However, these phenotypes were surprisingly narrow in scope relative to those associated with a complete deletion of the hacA gene. These findings expand the understanding of UPR signaling in this species by supporting the existence of noncanonical functions for the unspliced hacA mRNA in ER stress response.

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Section: Introductionmentioning

confidence: 99%

A Human IRE1 Inhibitor Blocks the Unfolded Protein Response in the Pathogenic Fungus Aspergillus fumigatus and Suggests Noncanonical Functions within the Pathway

Guirao-Abad

Weichert

Albee

et al. 2020

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Male Infertility, Oxidative Stress and Antioxidants

Zhaku¹,

Agarwal²,

Beadini³

et al. 2021

Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects

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Within the male reproductive system, oxidative stress (OS) has been identified as prevailing etiology of male infertility. The effects of reactive oxygen species (ROS) on male fertility depend on the dimensions, “modus operandi” of the ROS and the oxido-reduction potential (ORP) of the male reproductive tract. Hereupon, for an adequate response to OS, the cells of our body are endowed with a well-sophisticated system of defense in order to be protected. Various antioxidant enzymes and small molecular free radical scavengers, maintain the delicate balance between oxidants and reductants (antioxidants), crucial to cellular function and fertility. Therapeutic use of antioxidants is an optimal and coherent option in terms of mitigating OS and improving semen parameters. Therefore, recognizing and managing OS through either decreasing ROS levels or by increasing antioxidant force, appear to be a requesting approach in the management of male infertility. However, a clear defined attitude of the experts about the clinical efficacy of antioxidant therapy is still deprived. Prominently, antioxidant such as coenzyme Q10, vitamin C and E, lycopene, carnitine, zinc and selenium have been found useful in controlling the balance between ROS production and scavenging activities. In spite of that, healthy lifestyle, without smoke and alcohol, everyday exercise, reduction of psychological stress and quality well-designed meals, are habits that can overturn male infertility.

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Role of Endoplasmic Reticulum ER Stress-Induced Cell Death Mechanisms

Cited by 2 publications

References 342 publications

A Human IRE1 Inhibitor Blocks the Unfolded Protein Response in the Pathogenic Fungus Aspergillus fumigatus and Suggests Noncanonical Functions within the Pathway

A Human IRE1 Inhibitor Blocks the Unfolded Protein Response in the Pathogenic Fungus Aspergillus fumigatus and Suggests Noncanonical Functions within the Pathway

Male Infertility, Oxidative Stress and Antioxidants

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