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Cell Non-autonomous UPRER Signaling

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Coordinating Organismal Physiology Through the Unfolded Protein Response

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 414))

Abstract

The UPRER is an important regulator of secretory pathway homeostasis, and plays roles in many physiological processes. Its broad range of targets and ability to modulate secretion and membrane trafficking make it perfectly positioned to influence intercellular communication, enabling the UPRER to coordinate physiological processes between cells and tissues. Recent evidence suggests that the activation of the UPRER can itself be communicated between cells. This cell non-autonomous route to UPRER activation occurs in multiple species, and enables organism-wide responses to stress that involve processes as diverse as immunity, metabolism, aging and reproduction. It may also play roles in disease progression, making the pathways that mediate cell non-autonomous UPRER signaling a potential source of novel future therapeutics.

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References

  • Acosta-Alvear D et al (2007) XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 27:53–66

    Article  CAS  Google Scholar 

  • Andruska N et al (2015a) Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor alpha-positive breast cancer. Oncogene 34:3760–3769

    Article  CAS  Google Scholar 

  • Andruska ND et al (2015b) Estrogen receptor alpha inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression. Proc Natl Acad Sci U S A. 112:4737–4742

    Article  CAS  Google Scholar 

  • Arner P et al (2008) FGF21 attenuates lipolysis in human adipocytes—a possible link to improved insulin sensitivity. FEBS Lett 582:1725–1730

    Article  CAS  Google Scholar 

  • Baird M et al (2013) The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner. Lab Invest 93:112–122

    Article  CAS  Google Scholar 

  • Bertolotti A et al (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326–332

    Article  CAS  Google Scholar 

  • Biteau B, Hochmuth CE, Jasper H (2008) JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3:442–455

    Article  CAS  Google Scholar 

  • Biteau B et al (2010) Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet 6:e1001159

    Article  Google Scholar 

  • Calfon M et al (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415:92–96

    Article  CAS  Google Scholar 

  • Correa P, Houghton J (2007) Carcinogenesis of Helicobacter pylori. Gastroenterology 133:659–672

    Article  CAS  Google Scholar 

  • Cox JS, Walter P (1996) A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87:391–404

    Article  CAS  Google Scholar 

  • Fisher FM, Maratos-Flier E (2016) Understanding the Physiology of FGF21. Annu Rev Physiol 78:223–241

    Article  CAS  Google Scholar 

  • Garg AD et al (2012a) ER stress-induced inflammation: does it aid or impede disease progression? Trends Mol Med. 18:589–598

    Article  CAS  Google Scholar 

  • Garg AD et al (2012b) A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J 31:1062–1079

    Article  CAS  Google Scholar 

  • Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  CAS  Google Scholar 

  • Harding HP et al (2000a) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  CAS  Google Scholar 

  • Harding HP et al (2000b) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904

    Article  CAS  Google Scholar 

  • Haze K et al (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10:3787–3799

    Article  CAS  Google Scholar 

  • Heazlewood CK et al (2008) Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. Plos Medicine. 5:440–460

    Article  CAS  Google Scholar 

  • Hochmuth CE et al (2011) Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8:188–199

    Article  CAS  Google Scholar 

  • Hollien J et al (2009) Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 186:323–331

    Article  CAS  Google Scholar 

  • Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917

    Article  CAS  Google Scholar 

  • Karali E et al (2014) VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress. Mol Cell 54:559–572

    Article  CAS  Google Scholar 

  • Kharitonenkov A et al (2005) FGF-21 as a novel metabolic regulator. J Clin Invest. 115:1627–1635

    Article  CAS  Google Scholar 

  • Kim KH et al (2013) Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 19:83–92

    Article  CAS  Google Scholar 

  • Kulalert W, Kim DH (2013) The unfolded protein response in a pair of sensory neurons promotes entry of C. elegans into dauer diapause. Curr Biol 23:2540–2545

    Article  CAS  Google Scholar 

  • Levi-Ferber M et al (2014) It’s all in your mind: determining germ cell fate by neuronal IRE-1 in C-elegans. Plos Genetics 10

    Google Scholar 

  • Lin JH et al (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science 318:944–949

    Article  CAS  Google Scholar 

  • Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4:966–977

    Article  CAS  Google Scholar 

  • Mahadevan NR et al (2011) Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells. Proc Natl Acad Sci U S A. 108:6561–6566

    Article  CAS  Google Scholar 

  • Mahadevan NR et al (2012) Cell-extrinsic effects of tumor ER stress imprint myeloid dendritic cells and impair CD8(+) T cell priming. PLoS ONE 7:e51845

    Article  CAS  Google Scholar 

  • Marciniak SJ et al (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18:3066–3077

    Article  CAS  Google Scholar 

  • Nakatani Y et al (2005) Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem 280:847–851

    Article  CAS  Google Scholar 

  • Ozcan L et al (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9:35–51

    Article  CAS  Google Scholar 

  • Ozcan U et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461

    Article  Google Scholar 

  • Panaretakis T et al (2009) Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J 28:578–590

    Article  CAS  Google Scholar 

  • Richardson CE, Kooistra T, Kim DH (2010) An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463:1092–1095

    Article  CAS  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  Google Scholar 

  • Schaap FG et al (2013) Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. Biochimie 95:692–699

    Article  CAS  Google Scholar 

  • Shapiro DJ et al (2016) Anticipatory UPR activation: a protective pathway and target in cancer. Trends Endocrinol Metab 27:731–741

    Article  CAS  Google Scholar 

  • Sidrauski C, Walter P (1997) The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90:1031–1039

    Article  CAS  Google Scholar 

  • Singh V, Aballay A (2012) Endoplasmic reticulum stress pathway required for immune homeostasis is neurally controlled by arrestin-1. J Biol Chem 287:33191–33197

    Article  CAS  Google Scholar 

  • Sun J et al (2011) Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332:729–732

    Article  CAS  Google Scholar 

  • Sun JR, Liu YY, Aballay A (2012) Organismal regulation of XBP-1-mediated unfolded protein response during development and immune activation. EMBO Rep 13:855–860

    Article  CAS  Google Scholar 

  • Taylor RC, Dillin A (2013) XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153:1435–1447

    Article  CAS  Google Scholar 

  • Taylor RC, Berendzen KM, Dillin A (2014) Systemic stress signalling: understanding the cell non-autonomous control of proteostasis. Nat Rev Mol Cell Biol 15:211–217

    Article  CAS  Google Scholar 

  • Urano F et al (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666

    Article  CAS  Google Scholar 

  • Volchuk A, Ron D (2010) The endoplasmic reticulum stress response in the pancreatic beta-cell. Diabetes Obes Metab 12(Suppl 2):48–57

    Article  CAS  Google Scholar 

  • Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    Article  CAS  Google Scholar 

  • Wan XS et al (2014) ATF4- and CHOP-dependent induction of FGF21 through endoplasmic reticulum stress. Biomed Res Int 2014:807874

    PubMed  PubMed Central  Google Scholar 

  • Wang LF et al (2014) Integration of UPRER and oxidative stress signaling in the control of intestinal stem cell proliferation. Plos Genetics 10

    Google Scholar 

  • Wang LF et al (2015) PERK limits drosophila lifespan by promoting intestinal stem cell proliferation in response to ER stress. Plos Genetics 11

    Google Scholar 

  • Weis VG, Goldenring JR (2009) Current understanding of SPEM and its standing in the preneoplastic process. Gastric Cancer 12:189–197

    Article  Google Scholar 

  • Wente W et al (2006) Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55:2470–2478

    Article  CAS  Google Scholar 

  • Williams KW et al (2014) Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab 20:471–482

    Article  CAS  Google Scholar 

  • Xu J et al (2009) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58:250–259

    Article  CAS  Google Scholar 

  • Yu L et al (2016) Anticipatory activation of the unfolded protein response by epidermal growth factor is required for immediate early gene expression and cell proliferation. Mol Cell Endocrinol 422:31–41

    Article  CAS  Google Scholar 

Download references

Acknowledgements

SI, MS and RCT are supported by the Medical Research Council.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK

    Soudabeh Imanikia, Ming Sheng & Rebecca C. Taylor

Authors
  1. Soudabeh Imanikia
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  2. Ming Sheng
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  3. Rebecca C. Taylor
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Corresponding author

Correspondence to Rebecca C. Taylor .

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Editors and Affiliations

  1. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA

    R. Luke Wiseman

  2. Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Cole M. Haynes

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Imanikia, S., Sheng, M., Taylor, R.C. (2017). Cell Non-autonomous UPRER Signaling. In: Wiseman, R., Haynes, C. (eds) Coordinating Organismal Physiology Through the Unfolded Protein Response. Current Topics in Microbiology and Immunology, vol 414. Springer, Cham. https://doi.org/10.1007/82_2017_38

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