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Roles of Endoplasmic Reticulum Stress in Immune Responses

  • So, Jae-Seon
  • Received : 2018.05.29
  • Accepted : 2018.07.19
  • Published : 2018.08.31

Abstract

The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, folding and modification, and lipid synthesis and calcium storage. Dysregulation of ER functions leads to the accumulation of misfolded- or unfolded-protein in the ER lumen, and this triggers the unfolded protein response (UPR), which restores ER homeostasis. The UPR is characterized by three distinct downstream signaling pathways that promote cell survival or apoptosis depending on the stressor, the intensity and duration of ER stress, and the cell type. Mammalian cells express the UPR transducers IRE1, PERK, and ATF6, which control transcriptional and translational responses to ER stress. Direct links between ER stress and immune responses are also evident, but the mechanisms by which UPR signaling cascades are coordinated with immunity remain unclear. This review discusses recent investigations of the roles of ER stress in immune responses that lead to differentiation, maturation, and cytokine expression in immune cells. Further understanding of how ER stress contributes to the pathogenesis of immune disorders will facilitate the development of novel therapies that target UPR pathways.

Keywords

ER stress;immune response;inositol requiring enzyme 1 (IRE1);unfolded protein response (UPR);X-box binding protein 1 (XBP1)

References

  1. Acosta-Alvear, D., Zhou, Y., Blais, A., Tsikitis, M., Lents, N.H., Arias, C., Lennon, C.J., Kluger, Y., and Dynlacht, B.D. (2007). XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell 27, 53-66. https://doi.org/10.1016/j.molcel.2007.06.011
  2. Adachi, Y., Yamamoto, K., Okada, T., Yoshida, H., Harada, A., and Mori, K. (2008). ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct. Funct. 33, 75-89. https://doi.org/10.1247/csf.07044
  3. Ansa-Addo, E.A., Thaxton, J., Hong, F., Wu, B.X., Zhang, Y., Fugle, C.W., Metelli, A., Riesenberg, B., Williams, K., Gewirth, D.T., et al. (2016). Clients and oncogenic roles of molecular chaperone gp96/grp94. Curr. Top. Med. Chem. 16, 2765-2778. https://doi.org/10.2174/1568026616666160413141613
  4. Bertolotti, A., Zhang, Y., Hendershot, L.M., Harding, H.P., and Ron, D. (2000). Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2, 326-332. https://doi.org/10.1038/35014014
  5. Bettigole, S.E., and Glimcher, L.H. (2015). Endoplasmic reticulum stress in immunity. Annu. Rev. Immunol. 33, 107-138. https://doi.org/10.1146/annurev-immunol-032414-112116
  6. Bettigole, S.E., Lis, R., Adoro, S., Lee, A.-H., Spencer, L.A., Weller, P.F., and Glimcher, L.H. (2015). The transcription factor XBP1 is selectively required for eosinophil differentiation. Nat. Immunol. 16, 829-837. https://doi.org/10.1038/ni.3225
  7. Braakman, I., and Bulleid, N.J. (2011). Protein folding and modification in the mammalian endoplasmic reticulum. Annu. Rev. Biochem. 80, 71-99. https://doi.org/10.1146/annurev-biochem-062209-093836
  8. Brucklacher-Waldert, V., Ferreira, C., Stebegg, M., Fesneau, O., Innocentin, S., Marie, J.C., and Veldhoen, M. (2017). Cellular stress in the context of an inflammatory environment supports TGF-${\beta}$-independent T helper-17 differentiation. Cell Rep. 19, 2357-2370. https://doi.org/10.1016/j.celrep.2017.05.052
  9. Byrd, A.E., and Brewer, J.W. (2012). Intricately regulated: a cellular toolbox for fine-tuning XBP1 expression and activity. Cells 1, 738-753. https://doi.org/10.3390/cells1040738
  10. Calfon, M., Zeng, H., Urano, F., Till, J.H., Hubbard, S.R., Harding, H.P., Clark, S.G., and Ron, D. (2002). IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92-96. https://doi.org/10.1038/415092a
  11. Cao, S.S., Luo, K.L., and Shi, L. (2016). Endoplasmic reticulum stress interacts with inflammation in human diseases. J. Cell. Physiol. 231, 288-294. https://doi.org/10.1002/jcp.25098
  12. Chen, X., Karnovsky, A., Sans, M.D., Andrews, P.C., and Williams, J.A. (2010). Molecular characterization of the endoplasmic reticulum: insights from proteomic studies. Proteomics 10, 4040-4052. https://doi.org/10.1002/pmic.201000234
  13. Coelho, D.S., and Domingos, P.M. (2014). Physiological roles of regulated Ire1 dependent decay. Front. Genet. 5, 76.
  14. Cubillos-Ruiz, J.R., Silberman, P.C., Rutkowski, M.R., Chopra, S., Perales-Puchalt, A., Song, M., Zhang, S., Bettigole, S.E., Gupta, D., Holcomb, K., et al. (2015). ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527-1538. https://doi.org/10.1016/j.cell.2015.05.025
  15. Deng, J., Lu, P.D., Zhang, Y., Scheuner, D., Kaufman, R.J., Sonenberg, N., Harding, H.P., and Ron, D. (2004). Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol. Cell. Biol. 24, 10161-10168. https://doi.org/10.1128/MCB.24.23.10161-10168.2004
  16. Endo, M., Oyadomari, S., Suga, M., Mori, M., and Gotoh, T. (2005). The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. J. Biochem. 138, 501-507. https://doi.org/10.1093/jb/mvi143
  17. Fanlei, H., Xiaofei, Y., Hongxia, W., Daming, Z., Chunqing, G., Huanfa, Y., Boaz, T., R., S.J., Xiaoyan, Q., and Xiang-Yang, W. (2011). ER stress and its regulator X-box-binding protein-1 enhance polyICinduced innate immune response in dendritic cells. Eur. J. Immunol. 41, 1086-1097. https://doi.org/10.1002/eji.201040831
  18. Fawcett, T.W., Martindale, J.L., Guyton, K.Z., Hai, T., and Holbrook, N.J. (1999). Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem. J. 339, 135-141.
  19. Franco, A., Almanza, G., Burns, J.C., Wheeler, M., and Zanetti, M. (2010). Endoplasmic reticulum stress drives a regulatory phenotype in human T-cell clones. Cell. Immunol. 266, 1-6. https://doi.org/10.1016/j.cellimm.2010.09.006
  20. Garg, A.D., Kaczmarek, A., Krysko, O., Vandenabeele, P., Krysko, D. V, and Agostinis, P. (2012). ER stress-induced inflammation: does it aid or impede disease progression? Trends Mol. Med. 18, 589-598. https://doi.org/10.1016/j.molmed.2012.06.010
  21. Gass, J.N., Gifford, N.M., and Brewer, J.W. (2002). Activation of an unfolded protein response during differentiation of antibodysecreting B cells. J. Biol. Chem. 277, 49047-49054. https://doi.org/10.1074/jbc.M205011200
  22. Goodall, J.C., Wu, C., Zhang, Y., McNeill, L., Ellis, L., Saudek, V., and Gaston, J.S.H. (2010). Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc. Natl. Acad. Sci. USA 107, 17698-17703. https://doi.org/10.1073/pnas.1011736107
  23. Han, D., Lerner, A.G., Vande Walle, L., Upton, J.-P., Xu, W., Hagen, A., Backes, B.J., Oakes, S.A., and Papa, F.R. (2009). IRE1${\alpha}$ kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138, 562-575. https://doi.org/10.1016/j.cell.2009.07.017
  24. Harding, H.P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D.D., and Ron, D. (2001). Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153-1163. https://doi.org/10.1016/S1097-2765(01)00264-7
  25. Harding, H.P., Zhang, Y., Scheuner, D., Chen, J.-J., Kaufman, R.J., and Ron, D. (2009). Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2${\alpha}$) dephosphorylation in mammalian development. Proc. Natl. Acad. Sci. USA 106, 1832-1837. https://doi.org/10.1073/pnas.0809632106
  26. Heazlewood, C.K., Cook, M.C., Eri, R., Price, G.R., Tauro, S.B., Taupin, D., Thornton, D.J., Png, C.W., Crockford, T.L., Cornall, R.J., et al. (2008). Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLOS Med. 5, e54. https://doi.org/10.1371/journal.pmed.0050054
  27. Hetz, C. (2012). The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 13, 89-102. https://doi.org/10.1038/nrm3270
  28. Hetz, C., Chevet, E., and Harding, H.P. (2013). Targeting the unfolded protein response in disease. Nat. Rev. Drug Discov. 12, 703-719. https://doi.org/10.1038/nrd3976
  29. Hirayama, D., Iida, T., and Nakase, H. (2018). The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int. J. Mol. Sci. 19, 92.
  30. Hollien, J., and Weissman, J.S. (2006). Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104-107. https://doi.org/10.1126/science.1129631
  31. Hollien, J., Lin, J.H., Li, H., Stevens, N., Walter, P., and Weissman, J.S. (2009). Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186, 323-331. https://doi.org/10.1083/jcb.200903014
  32. Hotamisligil, G.S. (2010). Endoplasmic reticulum stress and atherosclerosis. Nat. Med. 16, 396-399. https://doi.org/10.1038/nm0410-396
  33. Hu, P., Han, Z., Couvillon, A.D., Kaufman, R.J., and Exton, J.H. (2006). Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1${\alpha}$-mediated NF-${\kappa}$B activation and down-regulation of TRAF2 expression. Mol. Cell. Biol. 26, 3071-3084. https://doi.org/10.1128/MCB.26.8.3071-3084.2006
  34. Hur, K.Y., So, J.-S., Ruda, V., Frank-Kamenetsky, M., Fitzgerald, K., Koteliansky, V., Iwawaki, T., Glimcher, L.H., and Lee, A.-H. (2012). IRE1${\alpha}$ activation protects mice against acetaminophen-induced hepatotoxicity. J. Exp. Med. 209, 307-318. https://doi.org/10.1084/jem.20111298
  35. Iqbal, J., Dai, K., Seimon, T., Jungreis, R., Oyadomari, M., Kuriakose, G., Ron, D., Tabas, I., and Hussain, M.M. (2008). IRE1${\beta}$ inhibits chylomicron production by selectively degrading MTP mRNA. Cell Metab. 7, 445-455. https://doi.org/10.1016/j.cmet.2008.03.005
  36. Iwakoshi, N.N., Pypaert, M., and Glimcher, L.H. (2007). The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J. Exp. Med. 204, 2267-2275. https://doi.org/10.1084/jem.20070525
  37. Janssens, S., Pulendran, B., and Lambrecht, B.N. (2014). Emerging functions of the unfolded protein response in immunity. Nat. Immunol. 15, 910-919. https://doi.org/10.1038/ni.2991
  38. Kamimura, D., and Bevan, M.J. (2008). Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection. J. Immunol. 181, 5433-5441. https://doi.org/10.4049/jimmunol.181.8.5433
  39. Kaser, A., Lee, A.-H., Franke, A., Glickman, J.N., Zeissig, S., Tilg, H., Nieuwenhuis, E.E.S., Higgins, D.E., Schreiber, S., Glimcher, L.H., et al. (2008). XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743-756. https://doi.org/10.1016/j.cell.2008.07.021
  40. Kaufman, R.J., Scheuner, D., SchrOder, M., Shen, X., Lee, K., Liu, C.Y., and Arnold, S.M. (2002). The unfolded protein response in nutrient sensing and differentiation. Nat. Rev. Mol. Cell Biol. 3, 411-421.
  41. Ko, J.S., Koh, J.M., So, J.-S., Jeon, Y.K., Kim, H.Y., and Chung, D.H. (2017). Palmitate inhibits arthritis by inducing t-bet and gata-3 mRNA degradation in iNKT cells via IRE1${\alpha}$-dependent decay. Sci. Rep. 7, 14940. https://doi.org/10.1038/s41598-017-14780-4
  42. Lee, A.-H., Iwakoshi, N.N., and Glimcher, L.H. (2003). XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448-7459. https://doi.org/10.1128/MCB.23.21.7448-7459.2003
  43. Lee, A., Chu, G.C., Iwakoshi, N.N., and Glimcher, L.H. (2005). XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J. 24, 4368-4380. https://doi.org/10.1038/sj.emboj.7600903
  44. Lee, A.-H., Scapa, E.F., Cohen, D.E., and Glimcher, L.H. (2008). Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320, 1492-1496. https://doi.org/10.1126/science.1158042
  45. Lerner, A.G., Upton, J.-P., Praveen, P.V.K., Ghosh, R., Nakagawa, Y., Igbaria, A., Shen, S., Nguyen, V., Backes, B.J., Heiman, M., et al. (2012). IRE1${\alpha}$ induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death during endoplasmic reticulum stress. Cell Metab. 16, 250-264. https://doi.org/10.1016/j.cmet.2012.07.007
  46. Lipson, K.L., Fonseca, S.G., Ishigaki, S., Nguyen, L.X., Foss, E., Bortell, R., Rossini, A.A., and Urano, F. (2006). Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulumresident protein kinase IRE1. Cell Metab. 4, 245-254. https://doi.org/10.1016/j.cmet.2006.07.007
  47. Lipson, K.L., Ghosh, R., and Urano, F. (2008). The role of IRE1${\alpha}$ in the degradation of insulin mRNA in pancreatic ${\beta}$-cells. PLoS One 3, e1648. https://doi.org/10.1371/journal.pone.0001648
  48. Lu, P.D., Harding, H.P., and Ron, D. (2004). Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 167, 27-33. https://doi.org/10.1083/jcb.200408003
  49. Ma, Y., and Hendershot, L.M. (2003). Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J. Biol. Chem. 278, 34864-34873. https://doi.org/10.1074/jbc.M301107200
  50. Ma, Y., Brewer, J.W., Alan Diehl, J., and Hendershot, L.M. (2002). Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J. Mol. Biol. 318, 1351-1365. https://doi.org/10.1016/S0022-2836(02)00234-6
  51. Marciniak, S.J., and Ron, D. (2006). Endoplasmic reticulum stress signaling in disease. Physiol. Rev. 86, 1133-1149. https://doi.org/10.1152/physrev.00015.2006
  52. Marisa, R., Andreia, M., J., A.R., Evelina, G., and Philippe, P. (2018). At the crossway of ER-stress and proinflammatory responses. FEBS J. doi:10.1111/febs.14391. [Epub ahead of print]. https://doi.org/10.1111/febs.14391
  53. Martinon, F., Chen, X., Lee, A.-H., and Glimcher, L.H. (2010). TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411-418. https://doi.org/10.1038/ni.1857
  54. Martins, A.S., Alves, I., Helguero, L., Domingues, M.R., and Neves, B.M. (2016). The unfolded protein response in homeostasis and modulation of mammalian immune cells. Int. Rev. Immunol. 35, 457-476. https://doi.org/10.3109/08830185.2015.1110151
  55. Moore, K., and Hollien, J. (2015). Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status. Mol. Biol. Cell 26, 2873-2884. https://doi.org/10.1091/mbc.e15-02-0074
  56. Novoa, I., Zhang, Y., Zeng, H., Jungreis, R., Harding, H.P., and Ron, D. (2003). Stress-induced gene expression requires programmed recovery from translational repression. EMBO J. 22, 1180-1187. https://doi.org/10.1093/emboj/cdg112
  57. Oikawa, D., Kimata, Y., Kohno, K., and Iwawaki, T. (2009). Activation of mammalian IRE1${\alpha}$ upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins. Exp. Cell Res. 315, 2496-2504. https://doi.org/10.1016/j.yexcr.2009.06.009
  58. Oikawa, D., Tokuda, M., Hosoda, A., and Iwawaki, T. (2010). Identification of a consensus element recognized and cleaved by IRE1${\alpha}$. Nucleic Acids Res. 38, 6265-6273. https://doi.org/10.1093/nar/gkq452
  59. Oslowski, C.M., and Urano, F. (2011). Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol. 490, 71-92.
  60. Osorio, F., Tavernier, S.J., Hoffmann, E., Saeys, Y., Martens, L., Vetters, J., Delrue, I., De Rycke, R., Parthoens, E., Pouliot, P., et al. (2014). The unfolded-protein-response sensor IRE-1${\alpha}$ regulates the function of CD8${\alpha}+$ dendritic cells. Nat. Immunol. 15, 248-257. https://doi.org/10.1038/ni.2808
  61. Oyadomari, S., Harding, H.P., Zhang, Y., Oyadomari, M., and Ron, D. (2008). Dephosphorylation of translation initiation factor 2${\alpha}$ enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 7, 520-532. https://doi.org/10.1016/j.cmet.2008.04.011
  62. Ozcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N.N., Ozdelen, E., Tuncman, G., GOrgun, C., Glimcher, L.H., and Hotamisligil, G.S. (2004). Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457-461. https://doi.org/10.1126/science.1103160
  63. Puthalakath, H., O'Reilly, L.A., Gunn, P., Lee, L., Kelly, P.N., Huntington, N.D., Hughes, P.D., Michalak, E.M., McKimm-Breschkin, J., Motoyama, N., et al. (2007). ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim. Cell 129, 1337-1349. https://doi.org/10.1016/j.cell.2007.04.027
  64. Raffaella, I., and Cristina, M. (2015). Cell death induced by endoplasmic reticulum stress. FEBS J. 283, 2640-2652.
  65. Rao, J., Yue, S., Fu, Y., Zhu, J., Wang, X., Busuttil, R.W., Kupiec-Weglinski, J.W., Lu, L., and Zhai, Y. (2014). ATF6 mediates a proinflammatory synergy between ER stress and TLR activation in the pathogenesis of liver ischemia reperfusion injury. Am. J. Transplant 14, 1552-1561. https://doi.org/10.1111/ajt.12711
  66. Reimold, A.M., Etkin, A., Clauss, I., Perkins, A., Friend, D.S., Zhang, J., Horton, H.F., Scott, A., Orkin, S.H., Byrne, M.C., et al. (2000). An essential role in liver development for transcription factor XBP-1. Genes Dev. 14, 152-157.
  67. Reimold, A.M., Iwakoshi, N.N., Manis, J., Vallabhajosyula, P., Szomolanyi-Tsuda, E., Gravallese, E.M., Friend, D., Grusby, M.J., Alt, F., and Glimcher, L.H. (2001). Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300-307. https://doi.org/10.1038/35085509
  68. Ron, D., and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519-529. https://doi.org/10.1038/nrm2199
  69. Rutkowski, D.T., and Hegde, R.S. (2010). Regulation of basal cellular physiology by the homeostatic unfolded protein response. J. Cell Biol. 189, 783-794. https://doi.org/10.1083/jcb.201003138
  70. Sandrine, B., Rivka, H., Takao, I., Jae-Seon, S., Ann-Hwee, L., and Boaz, T. (2013). Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells. Eur. J. Immunol. 44, 867-876.
  71. Scheu, S., Stetson, D.B., Reinhardt, R.L., Leber, J.H., Mohrs, M., and Locksley, R.M. (2006). Activation of the integrated stress response during T helper cell differentiation. Nat. Immunol. 7, 644-651.
  72. Shaffer, A.L., Shapiro-Shelef, M., Iwakoshi, N.N., Lee, A.-H., Qian, S.-B., Zhao, H., Yu, X., Yang, L., Tan, B.K., Rosenwald, A., et al. (2004). XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21, 81-93. https://doi.org/10.1016/j.immuni.2004.06.010
  73. Shen, J., Chen, X., Hendershot, L., and Prywes, R. (2002). ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of golgi localization signals. Dev. Cell 3, 99-111. https://doi.org/10.1016/S1534-5807(02)00203-4
  74. Shkoda, A., Ruiz, P.A., Daniel, H., Kim, S.C., Rogler, G., Sartor, R.B., and Haller, D. (2007). Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology 132, 190-207. https://doi.org/10.1053/j.gastro.2006.10.030
  75. Smith, J.A. (2018). Regulation of cytokine production by the unfolded protein response; implications for infection and autoimmunity. Front. Immunol. 9, 422. https://doi.org/10.3389/fimmu.2018.00422
  76. Smith, J.A., Turner, M.J., DeLay, M.L., Klenk, E.I., Sowders, D.P., and Colbert, R.A. (2008). Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-${\beta}$ induction via X-box binding protein 1. Eur. J. Immunol. 38, 1194-1203. https://doi.org/10.1002/eji.200737882
  77. So, J.-S., Hur, K.Y., Tarrio, M., Ruda, V., Frank-Kamenetsky, M., Fitzgerald, K., Koteliansky, V., Lichtman, A.H., Iwawaki, T., Glimcher, L.H., et al. (2012). Silencing of lipid metabolism genes through IRE1${\alpha}$-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 16, 487-499. https://doi.org/10.1016/j.cmet.2012.09.004
  78. So, J.-S., Cho, S., Min, S.-H., Kimball, S.R., and Lee, A.-H. (2015). IRE1${\alpha}$-dependent decay of CReP/Ppp1r15b mRNA increases eukaryotic initiation factor 2${\alpha}$ phosphorylation and suppresses protein synthesis. Mol. Cell. Biol. 35, 2761-2770. https://doi.org/10.1128/MCB.00215-15
  79. Stadhouders, R., Lubberts, E., and Hendriks, R.W. (2018). A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. J. Autoimmun. 87, 1-15. https://doi.org/10.1016/j.jaut.2017.12.007
  80. Tang, C.-H.A., Chang, S., Paton, A.W., Paton, J.C., Gabrilovich, D.I., Ploegh, H.L., Del Valle, J.R., and Hu, C.-C.A. (2018). Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization. J. Cell Biol. 217, 1739-1755. https://doi.org/10.1083/jcb.201709137
  81. Taubenheim, N., Tarlinton, D.M., Crawford, S., Corcoran, L.M., Hodgkin, P.D., and Nutt, S.L. (2012). High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency. J. Immunol. 189, 3328-3338. https://doi.org/10.4049/jimmunol.1201042
  82. Tavernier, S.J., Osorio, F., Vandersarren, L., Vetters, J., Vanlangenakker, N., Van Isterdael, G., Vergote, K., De Rycke, R., Parthoens, E., van de Laar, L., et al. (2017). Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival. Nat. Cell Biol. 19, 698-710. https://doi.org/10.1038/ncb3518
  83. Tellier, J., Shi, W., Minnich, M., Liao, Y., Crawford, S., Smyth, G.K., Kallies, A., Busslinger, M., and Nutt, S.L. (2016). Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response. Nat. Immunol. 17, 323-330. https://doi.org/10.1038/ni.3348
  84. Thaxton, J.E., Wallace, C., Riesenberg, B., Zhang, Y., Paulos, C.M., Beeson, C.C., Liu, B., and Li, Z. (2017). Modulation of endoplasmic reticulum stress controls CD4+ T-cell activation and antitumor function. Cancer Immunol. Res. 5, 666-675. https://doi.org/10.1158/2326-6066.CIR-17-0081
  85. Todd, D.J., McHeyzer-Williams, L.J., Kowal, C., Lee, A.-H., Volpe, B.T., Diamond, B., McHeyzer-Williams, M.G., and Glimcher, L.H. (2009). XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. J. Exp. Med. 206, 2151-2159. https://doi.org/10.1084/jem.20090738
  86. Tsuru, A., Fujimoto, N., Takahashi, S., Saito, M., Nakamura, D., Iwano, M., Iwawaki, T., Kadokura, H., Ron, D., and Kohno, K. (2013). Negative feedback by IRE1${\beta}$ optimizes mucin production in goblet cells. Proc. Natl. Acad. Sci. USA 110, 2864 LP-2869.
  87. Upton, J.-P., Wang, L., Han, D., Wang, E.S., Huskey, N.E., Lim, L., Truitt, M., McManus, M.T., Ruggero, D., Goga, A., et al. (2012). IRE1${\alpha}$ cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. Science 338, 818-822. https://doi.org/10.1126/science.1226191
  88. Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P., Harding, H.P., and Ron, D. (2000). Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664-666. https://doi.org/10.1126/science.287.5453.664
  89. Urra, H., Dufey, E., Lisbona, F., Rojas-Rivera, D., and Hetz, C. (2013). When ER stress reaches a dead end. Biochim. Biophys. Acta. Mol. Cell Res. 1833, 3507-3517. https://doi.org/10.1016/j.bbamcr.2013.07.024
  90. Vattemi, G., Engel, W.K., McFerrin, J., and Askanas, V. (2004). Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle. Am. J. Pathol. 164, 1-7. https://doi.org/10.1016/S0002-9440(10)63089-1
  91. Volmer, R., and Ron, D. (2015). Lipid-dependent regulation of the unfolded protein response. Curr. Opin. Cell Biol. 33, 67-73. https://doi.org/10.1016/j.ceb.2014.12.002
  92. Walter, P., and Ron, D. (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081-1086. https://doi.org/10.1126/science.1209038
  93. Wang, S., and Kaufman, R.J. (2012). The impact of the unfolded protein response on human disease. J. Cell Biol. 197, 857-867. https://doi.org/10.1083/jcb.201110131
  94. Wheeler, M.C., Rizzi, M., Sasik, R., Almanza, G., Hardiman, G., and Zanetti, M. (2008). KDEL-retained antigen in B lymphocytes induces a proinflammatory response: a possible role for endoplasmic reticulum stress in adaptive T cell immunity. J. Immunol. 181, 256-264. https://doi.org/10.4049/jimmunol.181.1.256
  95. Xue, X., Piao, J.-H., Nakajima, A., Sakon-Komazawa, S., Kojima, Y., Mori, K., Yagita, H., Okumura, K., Harding, H., and Nakano, H. (2005). Tumor necrosis factor ${\alpha}$ (TNF${\alpha}$) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNF${\alpha}$. J. Biol. Chem. 280, 33917-33925. https://doi.org/10.1074/jbc.M505818200
  96. Yamaguchi, H., and Wang, H.-G. (2004). CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 279, 45495-45502. https://doi.org/10.1074/jbc.M406933200
  97. Yamamoto, K., Yoshida, H., Kokame, K., Kaufman, R.J., and Mori, K. (2004). Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J. Biochem. 136, 343-350. https://doi.org/10.1093/jb/mvh122
  98. Yamamoto, K., Suzuki, N., Wada, T., Okada, T., Yoshida, H., Kaufman, R.J., and Mori, K. (2008). Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds. J. Biochem. 144, 477-486. https://doi.org/10.1093/jb/mvn091
  99. Ye, J., Rawson, R.B., Komuro, R., Chen, X., Davé, U.P., Prywes, R., Brown, M.S., and Goldstein, J.L. (2000). ER Stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6, 1355-1364. https://doi.org/10.1016/S1097-2765(00)00133-7
  100. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T., and Mori, K. (2001). XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881-891. https://doi.org/10.1016/S0092-8674(01)00611-0
  101. Zhang, K., and Kaufman, R.J. (2008). From endoplasmic-reticulum stress to the inflammatory response. Nature 454, 455-462. https://doi.org/10.1038/nature07203
  102. Zhang, K., Shen, X., Wu, J., Sakaki, K., Saunders, T., Rutkowski, D.T., Back, S.H., and Kaufman, R.J. (2006). Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124, 587-599. https://doi.org/10.1016/j.cell.2005.11.040
  103. Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R.T., Remotti, H., Stevens, J.L., and Ron, D. (1998). CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12, 982-995. https://doi.org/10.1101/gad.12.7.982

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)