User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

Primary tabs

download
  • Open access
  • PDF
  • 14.54 M
Bensellam, Mohammed [UCL] Maxwell, Emma L. Chan, Jeng Yie Luzuriaga, Jude West, Phillip K. Jonas, Jean-Christophe [UCL] Laybutt, D. Ross

Aims/hypothesis Hypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress. Methods Mouse islets and MIN6 cells were exposed to various oxygen (O2) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed. db/db mice were used. Results Hypoxia-response genes were upregulated in vivo in the islets of diabetic, but not prediabetic, db/db mice. In isolated mouse islets and MIN6 cells, O2 deprivation (1–5% vs 20%; 4–24 h) markedly reduced the expression of adaptive UPR genes, including Hspa5, Hsp90b1, Fkbp11 and spliced Xbp1. Coatomer protein complex genes (Copa, Cope, Copg [also known as Copg1], Copz1 and Copz2) and ER-to-Golgi protein trafficking were also reduced, whereas apoptotic genes (Ddit3, Atf3 and Trb3 [also known as Trib3]), c-Jun N-terminal kinase (JNK) phosphorylation and cell death were increased. Inhibition of JNK, but not HIF1α, restored adaptive UPR gene expression and ER-to-Golgi protein trafficking while protecting against apoptotic genes and cell death following hypoxia. DDIT3 knockdown delayed the loss of the adaptive UPR and partially protected against hypoxia-induced cell death. The latter response was prevented by HSPA5 knockdown. Finally, Hspa5 overexpression significantly protected against hypoxia-induced cell death. Conclusions/interpretation Hypoxia inhibits the adaptive UPR in beta cells via JNK and DDIT3 activation, but independently of HIF1α. Downregulation of the adaptive UPR contributes to reduced ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2016
Language Anglais
Journal information "Diabetologia" - Vol. 59, no. 7, p. 1492-1502 (2016)
Peer reviewed yes
Publisher Springer (Heidelberg)
issn 0012-186X
e-issn 1432-0428
Publication status Publié
Affiliation UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition
Links
  1. Bensellam Mohammed, Laybutt D. Ross, Jonas Jean-Christophe, The molecular mechanisms of pancreatic β-cell glucotoxicity: Recent findings and future research directions, 10.1016/j.mce.2012.08.003
  2. Jitrapakdee S., Wutthisathapornchai A., Wallace J. C., MacDonald M. J., Regulation of insulin secretion: role of mitochondrial signalling, 10.1007/s00125-010-1685-0
  3. Jonas Jean-Christophe, Sharma Arun, Hasenkamp Wendy, Ilkova Hasan, Patanè Giovanni, Laybutt Ross, Bonner-Weir Susan, Weir Gordon C., Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes, 10.1074/jbc.274.20.14112
  4. Laybutt D. Ross, Sharma Arun, Sgroi Dennis C., Gaudet Justin, Bonner-Weir Susan, Weir Gordon C., Genetic Regulation of Metabolic Pathways in β-Cells Disrupted by Hyperglycemia, 10.1074/jbc.m111751200
  5. Li X., Zhang L., Meshinchi S., Dias-Leme C., Raffin D., Johnson J. D., Treutelaar M. K., Burant C. F., Islet Microvasculature in Islet Hyperplasia and Failure in a Model of Type 2 Diabetes, 10.2337/db06-0733
  6. Sato Yoshifumi, Endo Hiroko, Okuyama Hiroaki, Takeda Takaaki, Iwahashi Hiromi, Imagawa Akihisa, Yamagata Kazuya, Shimomura Iichiro, Inoue Masahiro, Cellular Hypoxia of Pancreatic β-Cells Due to High Levels of Oxygen Consumption for Insulin Secretionin Vitro, 10.1074/jbc.m110.194738
  7. Bensellam Mohammed, Duvillié Bertrand, Rybachuk Galyna, Laybutt D. Ross, Magnan Christophe, Guiot Yves, Pouysségur Jacques, Jonas Jean-Christophe, Glucose-Induced O2 Consumption Activates Hypoxia Inducible Factors 1 and 2 in Rat Insulin-Secreting Pancreatic Beta-Cells, 10.1371/journal.pone.0029807
  8. Zheng X, Zheng X, Wang X, Ma Z, Gupta Sunkari V, Botusan I, Takeda T, Björklund A, Inoue M, Catrina S-B, Brismar K, Poellinger L, Pereira T S, Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP, 10.1038/cddis.2012.66
  9. Emamaullee Juliet A., Shapiro A. M. James, Factors Influencing the Loss of β-Cell Mass in Islet Transplantation, 10.3727/000000007783464461
  10. Olsson R., Olerud J., Pettersson U., Carlsson P.-O., Increased Numbers of Low-Oxygenated Pancreatic Islets After Intraportal Islet Transplantation, 10.2337/db09-0490
  11. Scheuner Donalyn, Kaufman Randal J., The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes, 10.1210/er.2007-0039
  12. Eizirik Décio L., Cardozo Alessandra K., Cnop Miriam, The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus, 10.1210/er.2007-0015
  13. Fonseca SG, Gromada J, Urano F (2011) Endoplasmic reticulum stress and pancreatic beta-cell death. Trends Endocrinol Metab 22:266–274
  14. Chan J. Y., Luzuriaga J., Bensellam M., Biden T. J., Laybutt D. R., Failure of the Adaptive Unfolded Protein Response in Islets of Obese Mice Is Linked With Abnormalities in  -Cell Gene Expression and Progression to Diabetes, 10.2337/db12-0701
  15. Omikorede O, Qi C, Gorman T, Chapman P, Yu A, Smith D M, Herbert T P, ER stress in rodent islets of Langerhans is concomitant with obesity and β-cell compensation but not with β-cell dysfunction and diabetes, 10.1038/nutd.2013.35
  16. Engin Feyza, Nguyen Truc, Yermalovich Alena, Hotamisligil Gökhan S., Aberrant islet unfolded protein response in type 2 diabetes, 10.1038/srep04054
  17. Walters S. N., Luzuriaga J., Chan J. Y., Grey S. T., Laybutt D. R., Influence of chronic hyperglycemia on the loss of the unfolded protein response in transplanted islets, 10.1530/jme-13-0016
  18. Laybutt D. R., Preston A. M., Åkerfeldt M. C., Kench J. G., Busch A. K., Biankin A. V., Biden T. J., Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes, 10.1007/s00125-006-0590-z
  19. Chan Jeng Yie, Luzuriaga Jude, Maxwell Emma L., West Phillip K., Bensellam Mohammed, Laybutt D. Ross, The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK, 10.1016/j.mce.2015.06.025
  20. Bensellam Mohammed, Montgomery Magdalene K., Luzuriaga Jude, Chan Jeng Yie, Laybutt D. Ross, Inhibitor of differentiation proteins protect against oxidative stress by regulating the antioxidant–mitochondrial response in mouse beta cells, 10.1007/s00125-015-3503-1
  21. Preston A. M., Gurisik E., Bartley C., Laybutt D. R., Biden T. J., Reduced endoplasmic reticulum (ER)-to-Golgi protein trafficking contributes to ER stress in lipotoxic mouse beta cells by promoting protein overload, 10.1007/s00125-009-1506-5
  22. Boslem Ebru, MacIntosh Gemma, Preston Amanda M., Bartley Clarissa, Busch Anna K., Fuller Maria, Laybutt D. Ross, Meikle Peter J., Biden Trevor J., A lipidomic screen of palmitate-treated MIN6 β-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking, 10.1042/bj20101867
  23. Jonas J. C., Bensellam M., Duprez J., Elouil H., Guiot Y., Pascal S. M. A., Glucose regulation of islet stress responses and β-cell failure in type 2 diabetes, 10.1111/j.1463-1326.2009.01112.x
  24. Shaffer A.L, Shapiro-Shelef Miriam, Iwakoshi Neal N, Lee Ann-Hwee, Qian Shu-Bing, Zhao Hong, Yu Xin, Yang Liming, Tan Bruce K, Rosenwald Andreas, Hurt Elaine M, Petroulakis Emmanuel, Sonenberg Nahum, Yewdell Jonathan W, Calame Kathryn, Glimcher Laurie H, Staudt Louis M, XBP1, Downstream of Blimp-1, Expands the Secretory Apparatus and Other Organelles, and Increases Protein Synthesis in Plasma Cell Differentiation, 10.1016/j.immuni.2004.06.010
  25. Sriburi Rungtawan, Bommiasamy Hemamalini, Buldak Gerald L., Robbins Gregory R., Frank Matthew, Jackowski Suzanne, Brewer Joseph W., Coordinate Regulation of Phospholipid Biosynthesis and Secretory Pathway Gene Expression in XBP-1(S)-induced Endoplasmic Reticulum Biogenesis, 10.1074/jbc.m609490200
  26. Presley Robert, 10.1038/38891
  27. Ivan Mircea, Harris Adrian L., Martelli Fabio, Kulshreshtha Ritu, Hypoxia response and microRNAs: no longer two separate worlds, 10.1111/j.1582-4934.2008.00398.x
  28. Semenza Gregg L., Hypoxia-Inducible Factors in Physiology and Medicine, 10.1016/j.cell.2012.01.021
  29. Abdelli S., Abderrahmani A., Hering B. J., Beckmann J. S., Bonny C., The c-Jun N-terminal kinase JNK participates in cytokine- and isolation stress-induced rat pancreatic islet apoptosis, 10.1007/s00125-007-0704-2
  30. Abderrahmani A., Niederhauser G., Favre D., Abdelli S., Ferdaoussi M., Yang J. Y., Regazzi R., Widmann C., Waeber G., Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic beta cells, 10.1007/s00125-007-0642-z
  31. Maedler K., Schulthess F. T., Bielman C., Berney T., Bonny C., Prentki M., Donath M. Y., Roduit R., Glucose and leptin induce apoptosis in human  -cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases, 10.1096/fj.07-101824
  32. Chan J. Y., Cooney G. J., Biden T. J., Laybutt D. R., Differential regulation of adaptive and apoptotic unfolded protein response signalling by cytokine-induced nitric oxide production in mouse pancreatic beta cells, 10.1007/s00125-011-2139-z
  33. Subramanian S. L., Hull R. L., Zraika S., Aston-Mourney K., Udayasankar J., Kahn S. E., cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets, 10.1007/s00125-011-2338-7
  34. Brozzi Flora, Nardelli Tarlliza R., Lopes Miguel, Millard Isabelle, Barthson Jenny, Igoillo-Esteve Mariana, Grieco Fabio A., Villate Olatz, Oliveira Joana M., Casimir Marina, Bugliani Marco, Engin Feyza, Hotamisligil Gökhan S., Marchetti Piero, Eizirik Decio L., Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms, 10.1007/s00125-015-3669-6
  35. Ron D, Habener J F, CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription., 10.1101/gad.6.3.439
  36. Jauhiainen Alexandra, Thomsen Christer, Strömbom Linda, Grundevik Pernilla, Andersson Carola, Danielsson Anna, Andersson Mattias K., Nerman Olle, Rörkvist Linda, Ståhlberg Anders, Åman Pierre, Distinct Cytoplasmic and Nuclear Functions of the Stress Induced Protein DDIT3/CHOP/GADD153, 10.1371/journal.pone.0033208
  37. Sato Yoshifumi, Inoue Masahiro, Yoshizawa Tatsuya, Yamagata Kazuya, Moderate Hypoxia Induces β-Cell Dysfunction with HIF-1–Independent Gene Expression Changes, 10.1371/journal.pone.0114868
  38. Thuerauf D. J., Activation of the Unfolded Protein Response in Infarcted Mouse Heart and Hypoxic Cultured Cardiac Myocytes, 10.1161/01.res.0000233317.70421.03
  39. Koumenis C., Naczki C., Koritzinsky M., Rastani S., Diehl A., Sonenberg N., Koromilas A., Wouters B. G., Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2 , 10.1128/mcb.22.21.7405-7416.2002
  40. Romero-Ramirez Lorenzo, Cao Hongbin, Nelson Daniel, Hammond Ester, Lee Ann-Hwee, Yoshida Hiderou, Mori Kazutoshi, Glimcher Laurie H., Denko Nicholas C., Giaccia Amato J., Le Quynh-Thu, Koong Albert C., XBP1 Is Essential for Survival under Hypoxic Conditions and Is Required for Tumor Growth, 10.1158/0008-5472.can-04-1606
  41. Liu Yan, László Csaba, Liu Yi, Liu Wei, Chen Xiaozhuo, Evans Susan C., Wu Shiyong, Regulation of G1 Arrest and Apoptosis in Hypoxia by PERK and GCN2-Mediated eIF2α Phosphorylation, 10.1593/neo.91354
  42. Zhu Zhaowei, Zhong Hua, Zhou Qin, Hu Xinqun, Chen Dandan, Wang Jiemei, Wu Jinze, Cai Jingjing, Zhou Shenghua, Chen Alex F., Inhibition of PKR impairs angiogenesis through a VEGF pathway, 10.1152/ajpendo.00469.2014
  43. Bensellam M., Van Lommel L., Overbergh L., Schuit F. C., Jonas J. C., Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations, 10.1007/s00125-008-1245-z
  44. Norlin S, Parekh VS, Naredi P, Edlund H (2015) Asna1/TRC40 controls beta cell function and ER homeostasis by ensuring retrograde transport. Diabetes 65:110–119
  45. Pétremand Jannick, Puyal Julien, Chatton Jean-Yves, Duprez Jessica, Allagnat Florent, Frias Miguel, James Richard W., Waeber Gérard, Jonas Jean-Christophe, Widmann Christian, HDLs Protect Pancreatic β-Cells Against ER Stress by Restoring Protein Folding and Trafficking, 10.2337/db11-1221
  46. Pirot P., Ortis F., Cnop M., Ma Y., Hendershot L. M., Eizirik D. L., Cardozo A. K., Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing Cells, 10.2337/db06-1253
  47. Song Benbo, Scheuner Donalyn, Ron David, Pennathur Subramaniam, Kaufman Randal J., Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes, 10.1172/jci34587
  48. Elouil H., Bensellam M., Guiot Y., Vander Mierde D., Pascal S. M. A., Schuit F. C., Jonas J. C., Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets, 10.1007/s00125-007-0674-4
  49. Gomez Edith, Powell Mike L., Bevington Alan, Herbert Terence P., A decrease in cellular energy status stimulates PERK-dependent eIF2α phosphorylation and regulates protein synthesis in pancreatic β-cells, 10.1042/bj20071367
  50. Moore Claire E., Omikorede Omotola, Gomez Edith, Willars Gary B., Herbert Terence P., PERK Activation at Low Glucose Concentration Is Mediated by SERCA Pump Inhibition and Confers Preemptive Cytoprotection to Pancreatic β-Cells, 10.1210/me.2010-0309
  51. Stokes Rebecca A., Cheng Kim, Deters Natasha, Lau Sue Mei, Hawthorne Wayne J., O'connell Philip J., Stolp Jessica, Grey Shane, Loudovaris Thomas, Kay Thomas W., Thomas Helen E., Gonzalez Frank J., Gunton Jenny E., Hypoxia-Inducible Factor-1α (HIF-1α) Potentiates β-Cell Survival after Islet Transplantation of Human and Mouse Islets, 10.3727/096368912x647180
Bibliographic reference Bensellam, Mohammed ; Maxwell, Emma L. ; Chan, Jeng Yie ; Luzuriaga, Jude ; West, Phillip K. ; et. al. Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells. In: Diabetologia, Vol. 59, no. 7, p. 1492-1502 (2016)
Permanent URL http://hdl.handle.net/2078.1/173121