Browsing by Subject "IRE1"

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    THE EIF2 KINASE PERK AND THE INTEGRATED STRESS RESPONSE FACILITATE ACTIVATION OF ATF6 DURING ENDOPLASMIC RETICULUM STRESS
    (Office of the Vice Chancellor for Research, 2012-04-13) Teske, Brian F.; Wek, Ronald C.; Wek, Sheree A.; Bunpo, Piyawan; Cundiff, Judy K.; McClintick, Jeanette N.; Anthony, Tracy G.; Wek, Ronald C.
    Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves changes in gene expression aimed at expanding the ER protein processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. Mutations of these ER stress sensors have been linked to diabetes, cancer and neurodegenerative diseases. Consequently, understanding the regulation of these three pathways has substantial therapeutic potential for development of biomarkers and pharmaceuticals for management of these conditions. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins. PERK phosphorylation of eIF2 (eIF2~P) also induces preferential translation of ATF4, a transcription activator of the UPR. In this study we show that the PERK/eIF2~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse biological defects associated with loss of PERK.
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    Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
    (American Society for Microbiology, 2020-07-07) Augusto, Leonardo; Martynowicz, Jennifer; Amin, Parth H.; Alakhras, Nada S.; Kaplan, Mark H.; Wek, Ronald C.; Sullivan, William J., Jr.; Biochemistry and Molecular Biology, School of Medicine
    Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that Toxoplasma triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further identify a novel role for the host ER stress sensor protein IRE1 in Toxoplasma pathogenesis. Upon infection, Toxoplasma activates IRE1, engaging its noncanonical role in actin remodeling through the binding of filamin A. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study has identified novel mechanisms used by Toxoplasma to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis.