T. gondii rhoptry protein ROP18 induces apoptosis of neural cells via endoplasmic reticulum stress pathway

Wan, Lijuan; Gong, Lingli; Wang, Wei; An, Ran; Zheng, Meijuan; Jiang, Zongru; Tang, Yuewen; Zhang, Yihua; Chen, He; Yu, Li; Shen, Jilong; Du, Jian

doi:10.1186/s13071-015-1103-z

Cited by 30 publications

(43 citation statements)

References 40 publications

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“…Apoptosis is also induced during T. gondii infection. TgGRA15, TgROP16, and TgROP18 were involved in triggering neuroblastomal and choriocarcinoma apoptosis (An et al, ; Chang et al, ; Wan et al, ; Wei et al, ). Induction of apoptosis in immune cells (lymphocytes, natural killers, and macrophages) contributes to evasion of the host's immune defence during the acute phase of infection.…”

Section: Discussionmentioning

confidence: 99%

Eimeria tenellaROPkinaseEtROP1induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

Diallo

Sausset

Gnahoui-David

et al. 2019

Cellular Microbiology

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Coccidia are obligate intracellular protozoan parasites responsible for human and veterinary diseases. Eimeria tenella, the aetiologic agent of caecal coccidiosis, is a major pathogen of chickens. In Toxoplasma gondii, some kinases from the rhoptry compartment (ROP) are key virulence factors. ROP kinases hijack and modulate many cellular functions and pathways, allowing T. gondii survival and development. E. tenella's kinome comprises 28 putative members of the ROP kinase family; most of them are predicted, as pseudokinases and their functions have never been characterised. One of the predicted kinase, EtROP1, was identified in the rhoptry proteome of E. tenella sporozoites. Here, we demonstrated that EtROP1 is active, and the N‐terminal extension is necessary for its catalytic kinase activity. Ectopic expression of EtROP1 followed by co‐immunoprecipitation identified cellular p53 as EtROP1 partner. Further characterisation confirmed the interaction and the phosphorylation of p53 by EtROP1. E. tenella infection or overexpression of EtROP1 resulted both in inhibition of host cell apoptosis and G0/G1 cell cycle arrest. This work functionally described the first ROP kinase from E. tenella and its noncanonical structure. Our study provides the first mechanistic insight into host cell apoptosis inhibition by E. tenella. EtROP1 appears as a new candidate for coccidiosis control.

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Section: Discussionmentioning

confidence: 99%

Eimeria tenellaROPkinaseEtROP1induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

Diallo

Sausset

Gnahoui-David

et al. 2019

Cellular Microbiology

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“…Uncontrolled tachyzoite replication may cause severe and potentially life-threatening encephalitis. It is well known that encephalitis caused by T. gondii can be lethal, due to tissue inflammation, apoptosis, and/or necrosis, as well as other complex pathological processes (2,8,10,11,21). However, the mechanism of TE is still unclear despite a variety of hypotheses that have been proposed.…”

Section: Discussionmentioning

confidence: 99%

“…Our studies revealed that ROP18 phosphorylates the host NF-κB p65 and targets this protein to ubiquitin-dependent degradation, thus inhibiting the NF-κB pathway in infected macrophages (17). In addition, our recent studies have demonstrated that ROP18 can stimulate neural cell death by inducing the ER stress-mediated apoptosis pathway (10). However, host proteins, especially those preferentially expressed in nervous tissues, targeted by ROP18 and its associated molecular mechanism remain unclear.…”

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confidence: 83%

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Encephalitis is mediated by ROP18 of Toxoplasma gondii , a severe pathogen in AIDS patients

Tang

Chen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The neurotropic parasite is a globally distributed parasitic protozoan among mammalian hosts, including humans. During the course of infection, the CNS is the most commonly damaged organ among invaded tissues. The polymorphic rhoptry protein 18 (ROP18) is a key serine (Ser)/threonine (Thr) kinase that phosphorylates host proteins to modulate acute virulence. However, the basis of neurotropism and the specific substrates through which ROP18 exerts neuropathogenesis remain unknown. Using mass spectrometry, we performed proteomic analysis of proteins that selectively bind to active ROP18 and identified RTN1-C, an endoplasmic reticulum (ER) protein that is preferentially expressed in the CNS. We demonstrated that ROP18 is associated with the N-terminal portion of RTN1-C and specifically phosphorylates RTN1-C at Ser7/134 and Thr4/8/118. ROP18 phosphorylation of RTN1-C triggers ER stress-mediated apoptosis in neural cells. Remarkably, ROP18 phosphorylation of RTN1-C enhances glucose-regulated protein 78 (GRP78) acetylation by attenuating the activity of histone deacetylase (HDAC), and this event is associated with an increase of neural apoptosis. These results clearly demonstrate that both RTN1-C and HDACs are involved in ROP18-mediated pathogenesis of encephalitis during infection.

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“…The dopamine content in cortical and hippocampus areas of the male offspring rats infected with T. gonodii is higher than that non‐infected control (Zhou et al, ). Moreover, T. gondii tachyzoites induces neural apoptosis in hippocampus and cortical areas of the infected mice, which might be responsible for neurological disorders of toxoplasmosis (Wan et al, ). It is also reported, 30 days after T. gondii infection, mice display spontaneous electrographically recorded seizures.…”

Section: Discussionmentioning

confidence: 99%

Contribution of dopamine neurotransmission in proconvulsant effect of Toxoplasma gondii infection in male mice

Babaie

Sayyah

Fard-Esfahani

et al. 2017

J of Neuroscience Research

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Epilepsy is one of the most common neurologic disorders worldwide with no distinguishable cause in 60% of patients. One-third of world's population is infected with Toxoplasma gondii (T. gondii). This intracellular parasite has high tendency to excitable cells including neurons. We assessed seizure susceptibility and involvement of dopaminergic system in male mice with acute and chronic T. gondii infection. Mice were infected by intraperitoneal injection of T. gondii cysts. Acute and chronic stages of infection were determined by quantification of SAG1/BAG1 transcripts and level of repetitive REP-529 sequence in the brain of mice by real-time PCR. Threshold of clonic seizures was measured by tail vein infusion of pentylenetetrazole. The infected mice were pretreated with D1 and D2 dopamine receptor antagonists, and seizure threshold was measured. Moreover, seizure threshold was determined after treatment of toxoplasmosis by sulfamethoxazole and trimethoprim. SAG1 level reached the maximum at week 2 after infection and then declined. The maximum level of BAG1 was observed at the week 3 and preserved till the week 8. REP-529 was detected at first week after infection, reached maximum at the week 3 and kept at this level till the eighth week. Threshold of seizures significantly decreased in both acute and chronic phases of infection. D1 and D2 receptors antagonists inhibited proconvulsant effect of toxoplasmosis. Chemotherapy inhibited parasite growth and multiplication, and returned seizure susceptibility to the level of non-infected mice. Dopaminergic neurotransmission participates in proconvulsant effect of T. gondii. The effect of parasite is eliminated by antibiotic therapy. © 2017 Wiley Periodicals, Inc.

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T. gondii rhoptry protein ROP18 induces apoptosis of neural cells via endoplasmic reticulum stress pathway

Cited by 30 publications

References 40 publications

Eimeria tenellaROPkinaseEtROP1induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

Eimeria tenellaROPkinaseEtROP1induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

Encephalitis is mediated by ROP18 of Toxoplasma gondii , a severe pathogen in AIDS patients

Contribution of dopamine neurotransmission in proconvulsant effect of Toxoplasma gondii infection in male mice

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