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      Lipid-dependent regulation of the unfolded protein response

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      Author(s): 1 , 2 , 3 , 4 , 1 , 2 , 3
      Publication date PMC-release:
      Journal: Current Opinion in Cell Biology
      Publisher: Elsevier

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          Abstract

          Protein folding homeostasis in the lumen of the endoplasmic reticulum is defended by signal transduction pathways that are activated by an imbalance between unfolded proteins and chaperones (so called ER stress). Collectively referred to as the unfolded protein response (UPR) this homeostatic response is initiated by three known ER stress transducers: IRE1, PERK and ATF6. These ER-localised transmembrane (TM) proteins posses lumenal stress sensing domains and cytosolic effector domains that collectively activate a gene expression programme regulating the production of proteins involved in the processing and maturation of secreted proteins that enter the ER. However, beyond limiting unfolded protein stress in the ER the UPR has important connections to lipid metabolism that are the subject of this review.

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          Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex.

          Denise Egger, Benno Wölk, Rainer Gosert … (2002)
          Plus-strand RNA viruses characteristically replicate their genome in association with altered cellular membranes. In the present study, the capacity of hepatitis C virus (HCV) proteins to elicit intracellular membrane alterations was investigated by expressing, in tetracycline-regulated cell lines, a comprehensive panel of HCV proteins individually as well as in the context of the entire HCV polyprotein. As visualized by electron microscopy (EM), expression of the combined structural proteins core-E1-E2-p7, the NS3-4A complex, and protein NS4B induced distinct membrane alterations. By immunogold EM (IEM), the membrane-altering proteins were always found to localize to the respective altered membranes. NS4B, a protein of hitherto unknown function, induced a tight structure, designated membranous web, consisting of vesicles in a membranous matrix. Expression of the entire HCV polyprotein gave rise to membrane budding into rough endoplasmic reticulum vacuoles, to the membranous web, and to tightly associated vesicles often surrounding the membranous web. By IEM, all HCV proteins were found to be associated with the NS4B-induced membranous web, forming a membrane-associated multiprotein complex. A similar web-like structure in livers of HCV-infected chimpanzees was previously described (Pfeifer et al., Virchows Arch. B., 33:233-243, 1980). In view of this finding and the observation that all HCV proteins accumulate on the membranous web, we propose that the membranous web forms the viral replication complex in HCV-infected cells.
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            Initiation and execution of lipotoxic ER stress in pancreatic beta-cells.

            Daniel Cunha, Paul Hekerman, Laurence Ladrière … (2008)
            Free fatty acids (FFA) cause apoptosis of pancreatic beta-cells and might contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum (ER) stress. We studied here the molecular mechanisms implicated in FFA-induced ER stress initiation and apoptosis in INS-1E cells, FACS-purified primary beta-cells and human islets exposed to oleate and/or palmitate. Treatment with saturated and/or unsaturated FFA led to differential ER stress signaling. Palmitate induced more apoptosis and markedly activated the IRE1, PERK and ATF6 pathways, owing to a sustained depletion of ER Ca(2+) stores, whereas the unsaturated FFA oleate led to milder PERK and IRE1 activation and comparable ATF6 signaling. Non-metabolizable methyl-FFA analogs induced neither ER stress nor beta-cell apoptosis. The FFA-induced ER stress response was not modified by high glucose concentrations, suggesting that ER stress in primary beta-cells is primarily lipotoxic, and not glucolipotoxic. Palmitate, but not oleate, activated JNK. JNK inhibitors reduced palmitate-mediated AP-1 activation and apoptosis. Blocking the transcription factor CHOP delayed palmitate-induced beta-cell apoptosis. In conclusion, saturated FFA induce ER stress via ER Ca(2+) depletion. The IRE1 and resulting JNK activation contribute to beta-cell apoptosis. PERK activation by palmitate also contributes to beta-cell apoptosis via CHOP.
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              XBP1

              Rungtawan Sriburi, Suzanne Jackowski, Kazutoshi Mori … (2004)
              When the protein folding capacity of the endoplasmic reticulum (ER) is challenged, the unfolded protein response (UPR) maintains ER homeostasis by regulating protein synthesis and enhancing expression of resident ER proteins that facilitate protein maturation and degradation. Here, we report that enforced expression of XBP1(S), the active form of the XBP1 transcription factor generated by UPR-mediated splicing of XBP1 mRNA, is sufficient to induce synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane. Cells overexpressing XBP1(S) exhibit elevated levels of membrane phospholipids, increased surface area and volume of rough ER, and enhanced activity of the cytidine diphosphocholine pathway of phosphatidylcholine biosynthesis. These data suggest that XBP1(S) links the mammalian UPR to phospholipid biosynthesis and ER biogenesis.
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                Author and article information

                Contributors
                Romain Volmer
                David Ron
                Journal
                Journal ID (nlm-ta): Curr Opin Cell Biol
                Journal ID (iso-abbrev): Curr. Opin. Cell Biol
                Title: Current Opinion in Cell Biology
                Publisher: Elsevier
                ISSN (Print): 0955-0674
                ISSN (Electronic): 1879-0410
                Publication date PMC-release: 1 April 2015
                Publication date (Print): April 2015
                Volume: 33
                Pages: 67-73
                Affiliations
                [1 ]Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
                [2 ]Wellcome Trust MRC Institute of Metabolic Science, Cambridge, United Kingdom
                [3 ]NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
                [4 ]Université de Toulouse, INP, ENVT, INRA, UMR 1225, IHAP, Toulouse, France
                Article
                Publisher ID: S0955-0674(14)00143-4
                DOI: 10.1016/j.ceb.2014.12.002
                PMC ID: 4376399
                PubMed ID: 25543896
                SO-VID: 12bcc714-d1a3-4eb6-9f91-096e85e3d1ae
                Copyright © © 2014 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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                ScienceOpen disciplines: Cell biology
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                ScienceOpen disciplines: Cell biology

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