Phosphorylation of eukaryotic initiation factor-2α in response to endoplasmic reticulum and nitrosative stress in the human protozoan parasite, Entamoeba histolytica

Walters, Heather A.; Welter, Brenda H.; Sullivan, William J.; Temesvari, Lesly A.

doi:10.1016/j.molbiopara.2019.111223

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…EiIF2K-A and EiIF2K-B share 32.64% identity within the kinase domain (Table S1). Consistent with published transcriptomic data [8], expression of EiIF2K-B was undetectable in control or mutant trophozoites growing in Previously, we showed that E. histolytica parasites possess a basal level of phosphorylated eIF2α, which increases after exposure to a subset of stressful conditions [4,5] and during encystation [4]. Therefore, we measured the level of phosphorylated eIF2α relative to total eIF2α in both trophozoites and encysting control and EiIF2K-KD parasites (Fig 4).…”

Section: Eiif2k-kd Parasites Exhibit Lower Phospho-eif2α Levels and A...supporting

confidence: 86%

“…In the large intestine, unknown signals trigger the conversion of trophozoites into environmentally stable mature cysts that are shed into the environment to facilitate host-to-host spread [3]. While navigating the human host, E. histolytica faces numerous stresses, such as nutrient deprivation, oxidative stress, nitrosative stress, and heat shock [4,5]. To survive, the parasite must surmount these damaging conditions.…”

Section: Introductionmentioning

confidence: 99%

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Eukaryotic initiation factor 2α kinases regulate virulence functions, stage conversion, and the stress response in Entamoeba invadens

Walters

Welter

Orobio-Hurtado

et al. 2022

Preprint

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Entamoeba histolytica is a protozoan parasite that causes amoebic dysentery and liver abscess. This pathogen possesses a two-stage life cycle consisting of an environmentally stable cyst and a pathogenic amoeboid trophozoite. Since infection is acquired by ingestion of cysts from contaminated food and water, this parasite is prevalent in underdeveloped countries. A reptilian pathogen, Entamoeba invadens, which can encyst in culture, has long-served as a surrogate to study stage conversion. In the host, the Entamoebae must manage stress including nutrient deprivation and host immune pressure. In many systems, the stress response is characterized by down-regulation of translation, which is initiated by the phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α). In mammalian cells, this phosphorylation is carried out by a family of eIF2α kinases. A canonical eIF2α translational control system exists in the Entamoebae; however, no eIF2α kinases have been characterized. In this study, we identified two eIF2α kinases in E. invadens, EiIF2K-A and EiIF2K-B. Their identity as eIF2α kinases was validated using a heterologous yeast system. We used an RNAi Trigger-mediated silencing system to reduce expression of EiIF2K-A, which also reduced expression of EiIF2K-B. Parasites with decreased kinase expression exhibited decreased phosphorylation of eIF2α and increased sensitivity to oxidative stress. Diminished kinase expression also correlates with an increased rate of encystation, a decreased the rate of excystation, and an increase in several virulence functions, erythrophagocytosis and adhesion to host cells. Taken together, these data suggest that EiIF2K-A and EiIF2K-B are authentic eIF2α kinases that may regulate the Entamoeba stress response.ImportanceEntamoeba histolytica is a human pathogen that causes dysentery and affects millions of people worldwide. This parasite possesses a two-stage life cycle: an environmentally stable cyst and the pathogenic trophozoite. Cysts are ingested from contaminated food and water; thus, this parasite in prevalent in underdeveloped countries. Current therapies commonly cause adverse side effects; therefore, new treatments are needed. In the host, Entamoeba experiences stress brought on, in part, by the host immune system. Understanding stage conversion and the stress response of this pathogen may lead to new drug therapies. Using the model organism, E. invadens, we identified two kinases, similar to those involved in stress and stage conversion in other systems. We determined that these kinases may regulate the oxidative stress response, stage conversion, and virulence. This work is significant as it will inform future studies on the life cycle and pathogenicity of the Entamoeba species.

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Section: Eiif2k-kd Parasites Exhibit Lower Phospho-eif2α Levels and A...supporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Eukaryotic initiation factor 2α kinases regulate virulence functions, stage conversion, and the stress response in Entamoeba invadens

Walters

Welter

Orobio-Hurtado

et al. 2022

Preprint

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“…OS induces a strong inhibition of protein synthesis in the parasite [ 35 ]. Although the mechanism for this inhibition is still not understood, it probably involves a higher eukaryotes in the phosphorylation of the initiation factor (eIF-2α) [ 39 , 40 ] and the oxidation of components of the parasite’s translational machinery, such as ribosomal proteins and elongation factors which leads to their inhibition [ 35 , 41 ]. At the transcriptomics level, OS triggers a complex response in the parasite which involves the modulation of a large number of genes which encode proteins with roles in translation, signaling/regulatory processes, metabolic/repair processes, energy metabolism, stress response, and transport [ 18 , 42 ].…”

Section: Response Of E Histolytica To Osmentioning

confidence: 99%

Entamoeba histolytica—Gut Microbiota Interaction: More Than Meets the Eye

Ankri

2021

Microorganisms

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Amebiasis is a disease caused by the unicellular parasite Entamoeba histolytica. In most cases, the infection is asymptomatic but when symptomatic, the infection can cause dysentery and invasive extraintestinal complications. In the gut, E. histolytica feeds on bacteria. Increasing evidences support the role of the gut microbiota in the development of the disease. In this review we will discuss the consequences of E. histolytica infection on the gut microbiota. We will also discuss new evidences about the role of gut microbiota in regulating the resistance of the parasite to oxidative stress and its virulence.

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“…Endoplasmic reticulum (ER) is the base for synthesis of some important biomacromolecules, such as proteins, lipids and sugars. [ 7 , 8 ]. When cells are stimulated by internal and external factors, the shape of ER changes and protein processing and transportation are blocked.…”

Section: Introductionmentioning

confidence: 99%

FAM134B-mediated endoplasmic reticulum autophagy protects against sepsis myocardial injury in mice

Chen

et al. 2021

Aging

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Reticulophagy regulator 1 (RETEG1, also known as FAM134B) plays a crucial role in endoplasmic reticulum autophagy. We aimed to explore the effect of FAM134B-mediated endoplasmic reticulum autophagy in sepsis myocardial injury in mice. Sepsis myocardial injury mice were established via cecal ligation and puncture procedures. The expression of FAM134B and LC3-II/I was determined using immunohistochemistry. Myocardial tissue morphological changes and apoptosis were examined using hematoxylin and eosin (H&E) staining and TUNEL analysis. The effects of FAM134B knockdown or overexpression on mice with sepsis myocardial injury were also studied. The levels of TNF-α, IL-6, IL-8, and IL-10 were evaluated using enzyme-linked immunosorbent assay (ELISA). Autophagy- and apoptosis-related protein expression was detected using western blotting. The effect of FAM134B on Lipopolysaccharide (LPS) -induced cardiomyocytes was also studied. The expression of FAM134B and LC3-II/I increased in sepsis mice and lipopolysaccharide (LPS)-treated cardiomyocytes. 3-Methyladenine (3-MA) significantly inhibited FAM134B and LC3-II/I expression and promoted myocardial injury, inflammation response, and cardiomyocyte apoptosis. The overexpression of FAM134B could minimize myocardial injury, inflammation, and apoptosis, whereas FAM134B knockdown showed opposite effects. FAM134B-mediated endoplasmic reticulum autophagy had a protective effect on sepsis myocardial injury in mice by reducing inflammation and tissue apoptosis, which may provide new insights for sepsis myocardial injury therapies.

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Phosphorylation of eukaryotic initiation factor-2α in response to endoplasmic reticulum and nitrosative stress in the human protozoan parasite, Entamoeba histolytica

Cited by 10 publications

References 30 publications

Eukaryotic initiation factor 2α kinases regulate virulence functions, stage conversion, and the stress response in Entamoeba invadens

Eukaryotic initiation factor 2α kinases regulate virulence functions, stage conversion, and the stress response in Entamoeba invadens

Entamoeba histolytica—Gut Microbiota Interaction: More Than Meets the Eye

FAM134B-mediated endoplasmic reticulum autophagy protects against sepsis myocardial injury in mice

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