Endoplasmic reticulum stress influences the localization of prion protein in the small intestine and mesenteric lymph nodes
Keywords:prion protein, Peyer’s patches, mesenteric lymph node, endoplasmic reticulum stress
- The aim of this study was to evaluate the effect of endoplasmic reticulum (ER) stress on the distribution of prion protein in the small intestine.
- The expression level of prion protein was evaluated by immunohistochemical and blotting methods in the tunicamycin-administrated (1 μg/g body weight for 24 h) mouse model.
- In ER stress, enterocytes are the major sites for prion protein entry and prions can use different routes to enter the body, which can vary depending on unresolved pathological conditions.
- It is important to control prion traffic in case of stress-related disorders.
Abstract: Tunicamycin is an endoplasmic reticulum (ER) stressor that inhibits protein glycosylation and promotes ER stress. To better understand the localization and traffic of prion protein (PrP) in both basal and ER stress conditions, we evaluated the presence and relative expression of PrP in the intestinal compartments of normal and tunicamycin-treated mice. After tunicamycin treatment, the level of PrP was significantly increased in enterocytes and blind-ended villous lymphatic vessels (lacteals), but was decreased in M cells. These results suggested that intake from the gut and transfer into lymphoid compartments of basal PrP occurs largely through the M cell-Peyer’s patch-mesenteric lymph node axis, and also alternatively through the enterocyte-lacteal-mesenteric lymph node axis. In ER stress, the enterocyte-lacteal-mesenteric lymph node is the sole axis for PrP transmission. Results also indicated that germinal centers and high endothelial venules (HEVs) are the most prominent portal for entry of PrP in both basal and ER stressed conditions. We speculated that PrP may use alternative routes for entry into intestinal compartments according to the pathophysiological state and that the mechanism managing the routes of PrP could contribute to the development of new therapeutic strategies against prion diseases as well as ER stress-related intestinal disorders.
Pastore A, Zagari A. A structural overview of the vertebrate prion proteins. Prion. 2007;1(3):185-97.
Sakudo A, Onodera T, Suganuma Y, Kobayashi T, Saeki K, Ikuta K. Recent advances in clarifying prion protein functions using knockout mice and derived cell lines. Mini Rev Med Chem. 2006;6(5):589-601.
Bueler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C. Mice devoid of PrP are resistant to scrapie. Cell. 1993;73(7):1339-47.
Beekes M, McBride PA. Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett. 2000;278(3):181-4.
Neutra MR, Frey A, Kraehenbuhl JP. Epithelial M cells: gateways for mucosal infection and immunization. Cell. 1996;86(3):345-8.
Brandtzaeg P, Kiyono H, Pabst R, Russell MW. Terminology: nomenclature of mucosa-associated lymphoid tissue. Mucosal Immunol. 2008;1(1):31-7.
Kraehenbuhl JP, Neutra MR. Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol. 2000;16:301-32.
Donaldson DS, Kobayashi A, Ohno H, Yagita H, Williams IR, Mabbott NA. M cell-depletion blocks oral prion disease pathogenesis. Mucosal Immunol. 2012;5(2):216-25.
Donaldson DS, Sehgal A, Rios D, Williams IR, Mabbott NA. Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility. PLoS Pathog. 2016;12(12):e1006075.
Heppner FL, Christ AD, Klein MA, Prinz M, Fried M, Kraehenbuhl JP, Aguzzi A. Transepithelial prion transport by M cells. Nat Med. 2001;7(9):976-7.
Davies GA, Bryant AR, Reynolds JD, Jirik FR, Sharkey KA. Prion diseases and the gastrointestinal tract. Can J Gastroenterol. 2006;20(1):18-24.
Jeffrey M, Gonzalez L, Espenes A, Press C.M, Martin S, Chaplin M, Davis L, Landsverk T, MacAldowie C, Eaton S, McGovern G. Transportation of prion protein across the intestinal mucosa of scrapie-susceptible and scrapie-resistant sheep. J Pathol. 2006;209(1):4-14.
Kujala P, Raymond CR, Romeijn M, Godsave SF, van Kasteren SI, Wille H, Prusiner SB, Mabbott NA, Peters PJ. Prion uptake in the gut: identification of the first uptake and replication sites. PLoS Pathog. 2011;7(2): e1002449.
Mishra RS, Basu S, Gu Y, Luo X, Zou WQ, Mishra R, Li R, Chen SG, Gambetti P, Fujioka H, Singh N. Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: implications for species barrier in prion uptake from the intestine. J Neurosci. 2004;24(50):11280-90.
Hetz C, Castilla J, Soto C. Perturbation of endoplasmic reticulum homeostasis facilitates prion replication. J Biol Chem. 2007;282(17):12725-33.
Roffe M, Beraldo FH, Bester R, Nunziante M, Bach C, Mancini G, Gilch S, Vorberg I, Castilho BA, Martins VR, Hajj GN. Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR. Proc Natl Acad Sci U S A. 2010;107(29):13147-52.
Misiewicz M, Dery MA, Foveau B, Jodoin J, Ruths D, LeBlanc AC. Identification of a novel endoplasmic reticulum stress response element regulated by XBP1. J Biol Chem. 2013;288(28):20378-91.
Gao Z, Peng M, Chen L, Yang X, Li H, Shi R, Wu G, Cai L, Song Q, Li C. Prion Protein Protects Cancer Cells against Endoplasmic Reticulum Stress Induced Apoptosis. Virol Sin. 2019;34(2):222-34.
Orsi A, Fioriti L, Chiesa R, Sitia R. Conditions of endoplasmic reticulum stress favor the accumulation of cytosolic prion protein. J Biol Chem. 2006;281(41):30431-8.
Dery MA, Jodoin J, Ursini-Siegel J, Aleynikova O, Ferrario C, Hassan S, Basik M, LeBlanc AC. Endoplasmic reticulum stress induces PRNP prion protein gene expression in breast cancer. Breast Cancer Res. 2013;15(2):R22.
Martin GR, Keenan CM, Sharkey KA, Jirik FR. Endogenous prion protein attenuates experimentally induced colitis. Am J Pathol. 2011;179(5):2290-301.
Petit CS, Barreau F, Besnier L, Gandille P, Riveau B, Chateau D, Roy M, Berrebi D, Svrcek M, Cardot P, Rousset M, Clair C, Thenet S. Requirement of cellular prion protein for intestinal barrier function and mislocalization in patients with inflammatory bowel disease. Gastroenterology. 2012;143(1):122-32.
Petit CS, Besnier L, Morel E, Rousset M, Thenet S. Roles of the cellular prion protein in the regulation of cell-cell junctions and barrier function. Tissue Barriers. 2013;1(2):e24377.
Ma X, Dai Z, Sun K, Zhang Y, Chen J, Yang Y, Tso P, Wu G, Wu Z. Intestinal Epithelial Cell Endoplasmic Reticulum Stress and Inflammatory Bowel Disease Pathogenesis: An Update Review. Front Immunol. 2017;8:1271.
Menard S, Cerf-Bensussan N, Heyman M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 2010;3(3):247-59.
Santaolalla R, Fukata M, Abreu MT. Innate immunity in the small intestine. Curr Opin Gastroenterol. 2011;27(2):125-31.
Heggebo R, Press CM, Gunnes G, Inge Lie K, Tranulis MA, Ulvund M, Groschup MH, Landsverk T. Distribution of prion protein in the ileal Peyer's patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. J Gen Virol. 2000;81(Pt9):2327-37.
Klein MA, Frigg R, Flechsig E, Raeber AJ, Kalinke U, Bluethmann H, Bootz F, Suter M, Zinkernagel RM, Aguzzi A. A crucial role for B cells in neuroinvasive scrapie. Nature. 1997;390(6661):687-90.
Mabbott NA, Bruce ME. Prion disease: bridging the spleen-nerve gap. Nat Med. 2003;9(12):1463-4.
Prinz M, Huber G, Macpherson AJ, Heppner FL, Glatzel M, Eugster HP, Wagner N, Aguzzi A. Oral prion infection requires normal numbers of Peyer's patches but not of enteric lymphocytes. Am J Pathol. 2003;162(4):1103-11.
Nakato G, Hase K, Suzuki M, Kimura M, Ato M, Hanazato M, Tobiume M, Horiuchi M, Atarashi R, Nishida N, Watarai M, Imaoka K, Ohno H. Cutting Edge: Brucella abortus exploits a cellular prion protein on intestinal M cells as an invasive receptor. J Immunol. 2012;189(4):1540-4.
Ohno H. Intestinal M cells. J Biochem. 2016;159(2):151-60.
Foster N, Macpherson GG. Murine cecal patch M cells transport infectious prions in vivo. J Infect Dis. 2010;202(12):1916-9.
Miller H, Zhang J, Kuolee R, Patel GB, Chen W. Intestinal M cells: the fallible sentinels? World J Gastroenterol. 2007;13(10):1477-86.
Ford MJ, Burton LJ, Morris RJ, Hall SM. Selective expression of prion protein in peripheral tissues of the adult mouse. Neuroscience. 2002;113(1):177-92.
Miyazawa K, Kanaya T, Tanaka S, Takakura I, Watanabe K, Ohwada S, Kitazawa H, Rose MT, Sakaguchi S, Katamine S, Yamaguchi T, Aso H. Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice. Histochem Cell Biol. 2007;127(3):291-301.
Bons N, Mestre-Frances N, Belli P, Cathala F, Gajdusek DC, Brown, P. Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents. Proc Natl Acad Sci U S A. 1999;96(7):4046-51.
Ji Y, Luo X, Yang Y, Dai Z, Wu G, Wu Z. Endoplasmic reticulum stress-induced apoptosis in intestinal epithelial cells: a feed-back regulation by mechanistic target of rapamycin complex 1 (mTORC1). J Anim Sci Biotechnol. 2018;9:38.
Kaser A, Blumberg RS. Endoplasmic reticulum stress and intestinal inflammation. Mucosal Immunol. 2010;3(1):11-6.
Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013;6(4):666-77.
Tuma P, Hubbard AL. Transcytosis: crossing cellular barriers. Physiol Rev. 2003;83(3):871-932.
Bernier-Latmani J, Petrova TV. Intestinal lymphatic vasculature: structure, mechanisms and functions. Nat Rev Gastroenterol Hepatol. 2017;14(9):510-26.
Suh SH, Choe K, Hong SP, Jeong SH, Makinen T, Kim KS, Alitalo K, Surh CD, Koh GY, Song JH. Gut microbiota regulates lacteal integrity by inducing VEGF-C in intestinal villus macrophages. EMBO Rep. 2019;20(4):e46927.
Jang JY, Koh YJ, Lee SH, Lee J, Kim KH, Kim D, Koh GY, Yoo OJ. Conditional ablation of LYVE-1+ cells unveils defensive roles of lymphatic vessels in intestine and lymph nodes. Blood. 2013;122(13):2151-61.
Vetrano S, Borroni EM, Sarukhan A, Savino B, Bonecchi R, Correale C, Arena V, Fantini M, Roncalli M, Malesci A, Mantovani A, Locati M, Danese S. The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6. Gut. 2010;59(2):197-206.
Akesson CP, McGovern G, Dagleish MP, Espenes A, Mc LPC, Landsverk T, Jeffrey M. Exosome-producing follicle associated epithelium is not involved in uptake of PrPd from the gut of sheep (Ovis aries): an ultrastructural study. PLoS One. 2011;6(7):e22180.
Ichikawa S, Kasahara D, Iwanaga T, Uchino S, Fujita T. Peptidergic nerve terminals associated with the central lacteal lymphatics in the ileal villi of dogs. Arch Histol Cytol. 1991;54(3):311-20.
Ichikawa S, Kyoda K, Iwanaga T, Fujita T, Uchino S. Nerve terminals associated with the central lacteal lymphatics in the duodenal and ileal villi of the monkey. Acta Anat (Basel). 1993;146(1):14-21.
Macpherson AJ, Smith K. Mesenteric lymph nodes at the center of immune anatomy. J Exp Med. 2006;203(3):497-500.
O'Connor T, Aguzzi A. Prions and lymphoid organs: solved and remaining mysteries. Prion. 2013;7(2):157-63.
Lawson VA, Collins SJ, Masters CL, Hill AF. Prion protein glycosylation. J Neurochem. 2005;93(4):793-801.
Lehmann S, Harris DA. Blockade of glycosylation promotes acquisition of scrapie-like properties by the prion protein in cultured cells. J Biol Chem. 1997;272(34):21479-87.
Petersen RB, Parchi P, Richardson SL, Urig CB, Gambetti P. Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. J Biol Chem. 1996;271(21):12661-8.
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