Eukaryotic Initiation Factor 2α Kinases Regulate Virulence Functions, Stage Conversion, and the Stress Response in Entamoeba invadens

Walters, Heather A.; Welter, Brenda H.; Moss, Harrison C.; Villano, Martha A.; Orobio-Hurtado, Ronny; Sullivan, William J.; Temesvari, Lesly A.

doi:10.1128/msphere.00131-22

Cited by 5 publications

(3 citation statements)

References 44 publications

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“…E. histolytica's genome does not encode obvious orthologues of PERK or ATF6; however, the phosphorylation of eIF2α occurs after serum starvation, heat shock, OS [57], and ER stress [58]. In E. invadens, silencing the gene encoding EieIF2α (homologous with eIF2α) leads to increased sensitivity to OS and a reduction in encystation rate [59]. These data suggest that there could be an incomplete UPR pathway in Entamoebae [57].…”

Section: Upr and Endoplasmic Reticulum Stress Responses Identified In...mentioning

confidence: 99%

Encystation and Stress Responses under the Control of Ubiquitin-like Proteins in Pathogenic Amoebae

Samba-Louaka,

Labruyère,

Matondo

et al. 2023

Microorganisms

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Amoebae found in aquatic and terrestrial environments encompass various pathogenic species, including the parasite Entamoeba histolytica and the free-living Acanthamoeba castellanii. Both microorganisms pose significant threats to public health, capable of inducing life-threatening effects on humans. These amoebae exist in two cellular forms: trophozoites and cysts. The trophozoite stage is the form used for growth and reproduction while the cyst stage is the resistant and disseminating form. Cysts occur after cellular metabolism slowdown due to nutritional deprivation or the appearance of environmental conditions unfavourable to the amoebae’s growth and division. The initiation of encystation is accompanied by the activation of stress responses, and scarce data indicate that encystation shares factors and mechanisms identified in stress responses occurring in trophozoites exposed to toxic compounds derived from human immune defence. Although some “omics” analyses have explored how amoebae respond to diverse stresses, these studies remain limited and rarely report post-translational modifications that would provide knowledge on the molecular mechanisms underlying amoebae-specific stress responses. In this review, we discuss ubiquitin-like proteins associated with encystation and cell survival during oxidative damage. We aim to shed light on the signalling pathways involved in amoebic defence mechanisms, with a focus on their potential clinical implications against pathogenic amoebae, addressing the pressing need for effective therapies.

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Section: Upr and Endoplasmic Reticulum Stress Responses Identified In...mentioning

confidence: 99%

Encystation and Stress Responses under the Control of Ubiquitin-like Proteins in Pathogenic Amoebae

Samba-Louaka,

Labruyère,

Matondo

et al. 2023

Microorganisms

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“…Consequently, global protein synthesis is curtailed while favoring the selective translation of mRNAs encoding factors that drive an adaptive response. We established that Toxoplasma eIF2α phosphorylation accompanies bradyzoite formation ( 5 ), as well as stage transitions in the fellow parasite Plasmodium falciparum ( 6 ) and the protozoan pathogen Entamoeba ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

mRNA cap-binding protein eIF4E1 is a novel regulator of Toxoplasma gondii latency

Holmes,

Bastos,

Dey

et al. 2024

mBio

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The protozoan parasite Toxoplasma gondii causes serious opportunistic disease due to its ability to persist in patients as latent tissue cysts. The molecular mechanisms coordinating conversion between proliferative parasites (tachyzoites) and latent cysts (bradyzoites) are not fully understood. We previously showed that phosphorylation of eIF2α accompanies bradyzoite formation, suggesting that this clinically relevant process involves regulation of mRNA translation. In this study, we investigated the composition and role of eIF4F multi-subunit complexes in translational control. Using CLIPseq, we find that the cap-binding subunit, eIF4E1, localizes to the 5′-end of all tachyzoite mRNAs, many of which show evidence of stemming from heterogeneous transcriptional start sites. We further show that eIF4E1 operates as the predominant cap-binding protein in two distinct eIF4F complexes. Using genetic and pharmacological approaches, we found that eIF4E1 deficiency triggers efficient spontaneous formation of bradyzoites without stress induction. Consistent with this result, we also show that stress-induced bradyzoites exhibit reduced eIF4E1 expression. Overall, our findings establish a novel role for eIF4F in translational control required for parasite latency and microbial persistence. IMPORTANCE Toxoplasma gondii is an opportunistic pathogen important to global human and animal health. There are currently no chemotherapies targeting the encysted form of the parasite. Consequently, a better understanding of the mechanisms controlling encystation is required. Here we show that the mRNA cap-binding protein, eIF4E1, regulates the encystation process. Encysted parasites reduce eIF4E1 levels, and depletion of eIF4E1 decreases the translation of ribosome-associated machinery and drives Toxoplasma encystation. Together, these data reveal a new layer of mRNA translational control that regulates parasite encystation and latency.

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“…Consequently, global protein synthesis is curtailed while favoring the selective translation of mRNAs encoding factors that drive an adaptive response. We established that Toxoplasma eIF2α phosphorylation accompanies bradyzoite formation (5), as well as transitions in the fellow parasite Plasmodium falciparum (6) and the protozoan pathogen Entamoeba (7,8).…”

Section: Introductionmentioning

confidence: 99%

mRNA cap-binding protein eIF4E1 is a novel regulator ofToxoplasma gondiilatency

Holmes,

Bastos,

Dey

et al. 2023

Preprint

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The protozoan parasiteToxoplasma gondiicauses serious opportunistic disease due to its ability to persist in patients as latent tissue cysts. The molecular mechanisms coordinating conversion between proliferative parasites (tachyzoites) and dormant cysts (bradyzoites) are not fully understood. We previously showed that phosphorylation of eIF2α accompanies bradyzoite formation, suggesting that this clinically relevant process involves regulation of mRNA translation. In this study, we investigated the composition and role of eIF4F multi-subunit complexes in translational control. Using CLIPseq, we find that the cap-binding subunit, eIF4E1, localizes to the 5’-end of all tachyzoite mRNAs, many of which show evidence of stemming from heterogenous transcriptional start sites. We further show that eIF4E1 operates as the predominant cap-binding protein in two distinct eIF4F complexes. Using genetic and pharmacological approaches, we found that eIF4E1 deficiency triggers efficient spontaneous formation of bradyzoites without stress induction. Consistent with this result, we also show that stress-induced bradyzoites exhibit reduced eIF4E1 expression. Overall, our findings establish a novel role for eIF4F in translational control required for parasite latency and microbial persistence.SignificanceToxoplasma gondiiis an opportunistic pathogen of importance to global human and animal health. There are currently no chemotherapies targeting the encysted form of the parasite. Consequently, a better understanding of the mechanisms controlling encystation are required. Here we show that the mRNA cap-binding protein, eIF4E1, is involved in regulating the encystation process. Encysted parasites reduce eIF4E1 levels and depletion of eIF4E1 decreases the translation of ribosome-associated machinery and drivesToxoplasmaencystation. Together, these data reveal a new layer of mRNA translational control that regulates parasite encystation and latency.

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Eukaryotic Initiation Factor 2α Kinases Regulate Virulence Functions, Stage Conversion, and the Stress Response in Entamoeba invadens

Abstract: Entamoeba 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.

Cited by 5 publications

References 44 publications

Encystation and Stress Responses under the Control of Ubiquitin-like Proteins in Pathogenic Amoebae

Encystation and Stress Responses under the Control of Ubiquitin-like Proteins in Pathogenic Amoebae

mRNA cap-binding protein eIF4E1 is a novel regulator of Toxoplasma gondii latency

mRNA cap-binding protein eIF4E1 is a novel regulator ofToxoplasma gondiilatency

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