ArticlePLoS pathogens2019
Regulation of arginine transport by GCN2 eIF2 kinase is important for replication of the intracellular parasite Toxoplasma gondii.
Article in PLoS pathogens, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 35 citations in OpenAlex.
- Mitochondria protect against an intracellular pathogen by restricting access to folate.Science (New York, N.Y.) · 2025Article
- Emerging Insights into the Relationship Between Amino Acid Metabolism and Diabetic Cardiomyopathy.Biomolecules · 2025Review
- Anti-Toxoplasma gondii efficacy of beta, beta-dimethylacrylshikonin and isobutyrylshikonin in vitro and in vivo.Parasites & vectors · 2025Article
- Translation regulation in response to stress.The FEBS journal · 2024Review
- Regulatory Role of eIF2αK4 in Amino Acid Transporter Expression in Mouse Brain Capillary Endothelial Cells.Pharmaceutical research · 2024Article
- Article
- Quercetin and L-Arginine Ameliorated the Deleterious Effects of Copper Oxide Nanoparticles on the Liver of Mice Through Anti-inflammatory and Anti-apoptotic Pathways.Biological trace element research · 2024Article
- The intersection of hostMicrobiology and molecular biology reviews : MMBR · 2024Review
- General control nonderepressible 2 (GCN2) as a therapeutic target in age-related diseases.Frontiers in aging · 2024Review
- A non-canonical sensing pathway mediates Plasmodium adaptation to amino acid deficiency.Communications biology · 2023Article
- GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment.Cell metabolism · 2022Article
- Study on the effect of koumiss on the intestinal microbiota of mice infected with Toxoplasma gondii.Scientific reports · 2022Article
- An Uninvited Seat at the Dinner Table: How Apicomplexan Parasites Scavenge Nutrients from the Host.Microorganisms · 2021Review
- CK1δ stimulates ubiquitination-dependent proteasomal degradation of ATF4 to promote chemoresistance in gastric Cancer.Clinical and translational medicine · 2021Article
- Substrate-mediated regulation of the arginine transporter of Toxoplasma gondii.PLoS pathogens · 2021Article
- Coordinated action of multiple transporters in the acquisition of essential cationic amino acids by the intracellular parasite Toxoplasma gondii.PLoS pathogens · 2021Article
- Host sensing and signal transduction during Toxoplasma stage conversion.Molecular microbiology · 2021Review
- Ribosome quality control antagonizes the activation of the integrated stress response on colliding ribosomes.Molecular cell · 2021Article
- Roles of interacting stress-related genes in lifespan regulation: insights for translating experimental findings to humans.Journal of translational genetics and genomics · 2021Article
- Induction of the Unfolded Protein Response during Bovine Alphaherpesvirus 1 Infection.Viruses · 2020Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Toxoplasma gondii is a prevalent protozoan parasite that can infect any nucleated cell but cannot replicate outside of its host cell. Toxoplasma is auxotrophic for several nutrients including arginine, tryptophan, and purines, which it must acquire from its host cell. The demands of parasite replication rapidly deplete the host cell of these essential nutrients, yet Toxoplasma successfully manages to proliferate until it lyses the host cell. In eukaryotic cells, nutrient starvation can induce the integrated stress response (ISR) through phosphorylation of an essential translation factor eIF2. Phosphorylation of eIF2 lowers global protein synthesis coincident with preferential translation of gene transcripts involved in stress adaptation, such as that encoding the transcription factor ATF4 (CREB2), which activates genes that modulate amino acid metabolism and uptake. Here, we discovered that the ISR is induced in host cells infected with Toxoplasma. Our results show that as Toxoplasma depletes host cell arginine, the host cell phosphorylates eIF2 via protein kinase GCN2 (EIF2AK4), leading to induced ATF4. Increased ATF4 then enhances expression of the cationic amino acid transporter CAT1 (SLC7A1), resulting in increased uptake of arginine in Toxoplasma-infected cells. Deletion of host GCN2, or its downstream effectors ATF4 and CAT1, lowers arginine levels in the host, impairing proliferation of the parasite. Our findings establish that Toxoplasma usurps the host cell ISR to help secure nutrients that it needs for parasite replication.
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