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Emerging Role for the PERK/eIF2α/ATF4 in Human Cutaneous Leishmaniasis

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      Abstract

      Leishmania parasites utilize adaptive evasion mechanisms in infected macrophages to overcome host defenses and proliferate. We report here that the PERK/eIF2α/ATF4 signaling branch of the integrated endoplasmic reticulum stress response (IERSR) is activated by Leishmania and this pathway is important for Leishmania amazonensis infection. Knocking down PERK or ATF4 expression or inhibiting PERK kinase activity diminished L. amazonensis infection. Knocking down ATF4 decreased NRF2 expression and its nuclear translocation, reduced HO-1 expression and increased nitric oxide production. Meanwhile, the increased expression of ATF4 and HO-1 mRNAs were observed in lesions derived from patients infected with the prevalent related species L.(V.) braziliensis. Our data demonstrates that Leishmania parasites activate the PERK/eIF2α/ATF-4 pathway in cultured macrophages and infected human tissue and that this pathway is important for parasite survival and progression of the infection.

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      The unfolded protein response: from stress pathway to homeostatic regulation.

      The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.
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        Regulated translation initiation controls stress-induced gene expression in mammalian cells.

         H Zeng,  R Wek,  Isabel Novoa (2000)
        Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murine cells reveals a novel role for eIF2alpha kinases in regulating gene expression in the unfolded protein response (UPR) and in amino acid starved cells. When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4), resulting in the induction of the downstream gene CHOP (GADD153). This is the first example of a mammalian signaling pathway homologous to the well studied yeast general control response in which eIF2alpha phosphorylation activates genes involved in amino acid biosynthesis. Mammalian cells thus utilize an ancient pathway to regulate gene expression in response to diverse stress signals.
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          XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.

          The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER). We have investigated here the contribution of the UPR transcription factors XBP-1, ATF6alpha, and ATF6beta to UPR target gene expression. Gene profiling of cell lines lacking these factors yielded several XBP-1-dependent UPR target genes, all of which appear to act in the ER. These included the DnaJ/Hsp40-like genes, p58(IPK), ERdj4, and HEDJ, as well as EDEM, protein disulfide isomerase-P5, and ribosome-associated membrane protein 4 (RAMP4), whereas expression of BiP was only modestly dependent on XBP-1. Surprisingly, given previous reports that enforced expression of ATF6alpha induced a subset of UPR target genes, cells deficient in ATF6alpha, ATF6beta, or both had minimal defects in upregulating UPR target genes by gene profiling analysis, suggesting the presence of compensatory mechanism(s) for ATF6 in the UPR. Since cells lacking both XBP-1 and ATF6alpha had significantly impaired induction of select UPR target genes and ERSE reporter activation, XBP-1 and ATF6alpha may serve partially redundant functions. No UPR target genes that required ATF6beta were identified, nor, in contrast to XBP-1 and ATF6alpha, did the activity of the UPRE or ERSE promoters require ATF6beta, suggesting a minor role for it during the UPR. Collectively, these results suggest that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP-1. Further, our observations suggest the existence of additional, as-yet-unknown, key regulators of the UPR.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Laboratory of Molecular Parasitology, Institute of Biophysics - Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21949-902 Brazil
            [2 ]ISNI 000000041936754X, GRID grid.38142.3c, Hematology Laboratory for Translation, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, ; Boston, MA 02115 United States
            [3 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Institute of Medical Biochemistry, Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21949-902 Brazil
            [4 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Department of Biochemistry and Immunology - University of São Paulo, ; Ribeirão Preto, SP 14049-900 Brazil
            [5 ]ISNI 0000 0001 0514 7202, GRID grid.411249.b, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, ; São Paulo, SP 04023-062 Brazil
            [6 ]ISNI 0000 0001 2238 5157, GRID grid.7632.0, Faculty of Medicine, University of Brasília, ; Brasília, DF 70910-900 Brazil
            [7 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Instituto de Microbiologia Paulo de Goes, Federal University of Rio de Janeiro, ; 21942-902 Rio de Janeiro, Brazil
            [8 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Center for Immunity and Infection Lausanne, Department of Biochemistry, Faculty of Biology and Medicine, University of Lausanne, ; CH-1066 Epalinges, Switzerland
            Contributors
            lopesu@biof.ufrj.br
            Journal
            Sci Rep
            Sci Rep
            Scientific Reports
            Nature Publishing Group UK (London )
            2045-2322
            6 December 2017
            6 December 2017
            2017
            : 7
            29213084
            5719050
            17252
            10.1038/s41598-017-17252-x
            © The Author(s) 2017

            Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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