title: The unfolded protein response in the protozoan parasite Toxoplasma gondii features translational and transcriptional control.
abstract: The unfolded protein response (UPR) is an important regulatory network that responds to perturbations in protein homeostasis in the endoplasmic reticulum (ER). In mammalian cells, the UPR features translational and transcriptional mechanisms of gene expression aimed at restoring proteostatic control. A central feature of the UPR is phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2) by PERK (EIF2AK3/PEK), which reduces the influx of nascent proteins into the ER by lowering global protein synthesis, coincident with preferential translation of key transcription activators of genes that function to expand the processing capacity of this secretory organelle. Upon ER stress, the apicomplexan parasite Toxoplasma gondii is known to induce phosphorylation of Toxoplasma eIF2α and lower translation initiation. To characterize the nature of the ensuing UPR in this parasite, we carried out microarray analyses to measure the changes in the transcriptome and in translational control during ER stress. We determined that a collection of transcripts linked with the secretory process are induced in response to ER stress, supporting the idea that a transcriptional induction phase of the UPR occurs in Toxoplasma. Furthermore, we determined that about 500 gene transcripts showed enhanced association with translating ribosomes during ER stress. Many of these target genes are suggested to be involved in gene expression, including JmjC5, which continues to be actively translated during ER stress. This study indicates that Toxoplasma triggers a UPR during ER stress that features both translational and transcriptional regulatory mechanisms, which is likely to be important for parasite invasion and development.
authors.affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Joyce
authors.forename: Zoi
authors.initials: Z
authors.lastname: Tampaki
authors.forename: Kami
authors.initials: K
authors.lastname: Kim
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.forename: William J
authors.initials: WJ
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D001483:Base Sequence; D019295:Computational Biology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008969:Molecular Sequence Data; D010271:Parasites / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014122:Toxoplasma / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics*; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism
chemical_list: D015800:Protozoan Proteins; D012333:RNA, Messenger; D014415:Tunicamycin; D056484:Jumonji Domain-Containing Histone Demethylases; D019892:eIF-2 Kinase