Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a signaling mechanism that allows cellular adaptation to ER stress by engaging pro-adaptive transcription factors and alleviating protein folding demand. One such transcription factor, X-box binding protein (XBP1), originates from the inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1) UPR stress sensor. XBP1 up-regulates a pool of genes involved in ER protein translocation, protein folding, vesicular trafficking and ER- associated protein degradation. Recent data suggest that the regulation of XBP1 expression and transcriptional activity may be a tissue- and stress-dependent phenomenon. Moreover, the intricacies involved in “fine-tuning” XBP1 activity in various settings are now coming to light. Here, we provide an overview of recent developments in understanding the regulatory mechanisms underlying XBP1 expression and activity and discuss the significance of these new insights.
References
[1]
Walter, P.; Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011, 334, 1081–1086, doi:10.1126/science.1209038.
[2]
Harding, H.P.; Zhang, Y.; Bertolotti, A.; Zeng, H.; Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 2000, 5, 897–904, doi:10.1016/S1097-2765(00)80330-5.
[3]
Harding, H.P.; Zhang, Y.; Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999, 397, 271–274, doi:10.1038/16729.
[4]
Scheuner, D.; Song, B.; McEwen, E.; Liu, C.; Laybutt, R.; Gillespie, P.; Saunders, T.; Bonner-Weir, S.; Kaufman, R.J. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 2001, 7, 1165–1176, doi:10.1016/S1097-2765(01)00265-9.
[5]
Shi, Y.; Vattem, K.M.; Sood, R.; An, J.; Liang, J.; Stramm, L.; Wek, R.C. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol. Cell. Biol. 1998, 18, 7499–7509.
[6]
Adachi, Y.; Yamamoto, K.; Okada, T.; Yoshida, H.; Harada, A.; Mori, K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct. Funct. 2008, 33, 75–89, doi:10.1247/csf.07044.
[7]
Haze, K.; Okada, T.; Yoshida, H.; Yanagi, H.; Yura, T.; Negishi, M.; Mori, K. Identification of the g13 (camp-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response. Biochem. J. 2001, 355, 19–28, doi:10.1042/0264-6021:3550019.
[8]
Haze, K.; Yoshida, H.; Yanagi, H.; Yura, T.; Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 1999, 10, 3787–3799.
[9]
Wu, J.; Rutkowski, D.T.; Dubois, M.; Swathirajan, J.; Saunders, T.; Wang, J.; Song, B.; Yau, G.D.; Kaufman, R.J. ATF6α optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell 2007, 13, 351–364, doi:10.1016/j.devcel.2007.07.005.
[10]
Yamamoto, K.; Sato, T.; Matsui, T.; Sato, M.; Okada, T.; Yoshida, H.; Harada, A.; Mori, K. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev. Cell 2007, 13, 365–376, doi:10.1016/j.devcel.2007.07.018.
[11]
Calfon, M.; Zeng, H.; Urano, F.; Till, J.H.; Hubbard, S.R.; Harding, H.P.; Clark, S.G.; Ron, D. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002, 415, 92–96, doi:10.1038/415092a.
[12]
Shen, X.; Ellis, R.; Lee, K.; Liu, C.-Y.; Yang, K.; Solomon, A.; Yoshida, H.; Morimoto, R.; Kurnit, D.M.; Mori, K.; et al. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 2001, 107, 893–903, doi:10.1016/S0092-8674(01)00612-2.
[13]
Yoshida, H.; Matsui, T.; Yamamoto, A.; Okada, T.; Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001, 107, 881–891, doi:10.1016/S0092-8674(01)00611-0.
[14]
Tabas, I.; Ron, D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol. 2011, 13, 184–190, doi:10.1038/ncb0311-184.
[15]
Byrd, A.E.; Aragon, I.V.; Brewer, J.W. MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response. J. Cell Biol. 2012, 196, 689–698, doi:10.1083/jcb.201201077.
[16]
Chen, H.; Qi, L. SUMO modification regulates the transcriptional activity of XBP1. Biochem. J. 2011, 429, 95–102, doi:10.1042/BJ20100193.
[17]
Lee, J.; Sun, C.; Zhou, Y.; Lee, J.; Gokalp, D.; Herrema, H.; Park, S.W.; Davis, R.J.; Ozcan, U. p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat. Med. 2011, 17, 1251–1260, doi:10.1038/nm.2449.
[18]
Majumder, M.; Huang, C.; Snider, M.D.; Komar, A.A.; Tanaka, J.; Kaufman, R.J.; Krokowski, D.; Hatzoglou, M. A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation. Mol. Cell. Biol. 2012, 32, 992–1003, doi:10.1128/MCB.06665-11.
[19]
Navon, A.; Gatushkin, A.; Zelcbuch, L.; Shteingart, S.; Farago, M.; Hadar, R.; Tirosh, B. Direct proteasome binding and subsequent degradation of unspliced XBP-1 prevent its intracellular aggregation. FEBS Letters 2010, 584, 67–73, doi:10.1016/j.febslet.2009.11.069.
[20]
Park, S.W.; Zhou, Y.; Lee, J.; Lu, A.; Sun, C.; Chung, J.; Ueki, K.; Ozcan, U. The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation. Nat. Med. 2010, 16, 429–437, doi:10.1038/nm.2099.
[21]
Tirosh, B.; Iwakoshi, N.N.; Glimcher, L.H.; Ploegh, H.L. Rapid turnover of unspliced Xbp-1 as a factor that modulates the unfolded protein response. J. Biol. Chem. 2006, 281, 5852–5860.
[22]
Wang, F.-M.; Chen, Y.-J.; Ouyang, H.-J. Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation. Biochem. J. 2011, 433, 245–252, doi:10.1042/BJ20101293.
[23]
Winnay, J.N.; Boucher, J.; Mori, M.A.; Ueki, K.; Kahn, C.R. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response. Nat. Med. 2010, 16, 438–445, doi:10.1038/nm.2121.
[24]
Yanagitani, K.; Imagawa, Y.; Iwawaki, T.; Hosoda, A.; Saito, M.; Kimata, Y.; Kohno, K. Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA. Mol. Cell 2009, 34, 191–200, doi:10.1016/j.molcel.2009.02.033.
[25]
Yanagitani, K.; Kimata, Y.; Kadokura, H.; Kohno, K. Translational pausing ensures membrane targeting and cytoplasmic splicing of XBP1u mRNA. Science 2011, 331, 586–589, doi:10.1126/science.1197142.
[26]
Yoshida, H.; Oku, M.; Suzuki, M.; Mori, K. pXBP1(u) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(s) in mammalian ER stress response. J. Cell. Biol. 2006, 172, 565–575, doi:10.1083/jcb.200508145.
[27]
Liou, H.C.; Boothby, M.R.; Finn, P.W.; Davidon, R.; Nabavi, N.; Zeleznik-Le, N.J.; Ting, J.P.; Glimcher, L.H. A new member of the leucine zipper class of proteins that binds to the HLA DR α promoter. Science 1990, 247, 1581–1584.
[28]
Glimcher, L.H. XBP1: The last two decades. Ann. Rheum. Dis. 2010, 69 (Suppl. 1), i67–i71, doi:10.1136/ard.2009.119388.
Lee, A.H.; Chu, G.C.; Iwakoshi, N.N.; Glimcher, L.H. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J. 2005, 24, 4368–4380, doi:10.1038/sj.emboj.7600903.
[31]
Lee, A.-H.; Heidtman, K.; Hotamisligil, G.S.; Glimcher, L.H. Dual and opposing roles of the unfolded protein response regulated by IRE1α and XBP1 in proinsulin processing and insulin secretion. Proc. Natl. Acad. Sci. USA 2011, 108, 8885–8890, doi:10.1073/pnas.1105564108.
[32]
Lee, A.-H.; Scapa, E.F.; Cohen, D.E.; Glimcher, L.H. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 2008, 320, 1492–1496, doi:10.1126/science.1158042.
[33]
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. An essential role in liver development for transcription factor XBP-1. Genes Dev. 2000, 14, 152–157.
[34]
Iwakoshi, N.N.; Pypaert, M.; Glimcher, L.H. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J. Exp. Med. 2007, 204, 2267–2275, doi:10.1084/jem.20070525.
[35]
Martinon, F.; Chen, X.; Lee, A.-H.L.; Glimcher, L.H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 2010, 11, 411–418, doi:10.1038/ni.1857.
[36]
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. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008, 134, 743–756, doi:10.1016/j.cell.2008.07.021.
Cox, J.S.; Shamu, C.E.; Walter, P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 1993, 73, 1197–1206, doi:10.1016/0092-8674(93)90648-A.
[39]
Mori, K.; Ma, W.; Gething, M.J.; Sambrook, J. A transmembrane protein with a cdc2+/cdc28-related kinase activity is required for signaling from the ER to the nucleus. Cell 1993, 74, 743–756, doi:10.1016/0092-8674(93)90521-Q.
[40]
Sidrauski, C.; Walter, P. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 1997, 90, 1031–1039, doi:10.1016/S0092-8674(00)80369-4.
[41]
Tirasophon, W.; Welihinda, A.A.; Kaufman, R.J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998, 12, 1812–1824, doi:10.1101/gad.12.12.1812.
[42]
Wang, X.Z.; Harding, H.P.; Zhang, Y.; Jolicoeur, E.M.; Kuroda, M.; Ron, D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 1998, 17, 5708–5717, doi:10.1093/emboj/17.19.5708.
[43]
Lee, A.H.; Iwakoshi, N.N.; Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 2003, 23, 7448–7459, doi:10.1128/MCB.23.21.7448-7459.2003.
[44]
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. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 2004, 21, 81–93, doi:10.1016/j.immuni.2004.06.010.
[45]
Bartoszewski, R.; Brewer, J.W.; Rab, A.; Crossman, D.K.; Bartoszewska, S.; Kapoor, N.; Fuller, C.; Collawn, J.F.; Bebok, Z. The unfolded protein response (UPR)-activated transcription factor X-box-binding protein 1 (XBP1) induces microRNA-346 expression that targets the human antigen peptide transporter 1 (TAP1) mRNA and governs immune regulatory genes. J. Biol. Chem. 2011, 286, 41862–41870.
[46]
Iwakoshi, N.N.; Lee, A.H.; Vallabhajosyula, P.; Otipoby, K.L.; Rajewsky, K.; Glimcher, L.H. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat. Immunol. 2003, 4, 321–329.
[47]
Back, S.H.; Lee, K.; Vink, E.; Kaufman, R.J. Cytoplasmic IRE1α-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress. J. Biol. Chem. 2006, 281, 18691–18706, doi:10.1074/jbc.M602030200.
[48]
Uemura, A.; Oku, M.; Mori, K.; Yoshida, H. Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during the mammalian unfolded protein response. J. Cell Sci. 2009, 122, 2877–2886, doi:10.1242/jcs.040584.
Duan, Q.; Wang, X.; Gong, W.; Ni, L.; Chen, C.; He, X.; Chen, F.; Yang, L.; Wang, P.; Wang, D.W. ER stress negatively modulates the expression of the mir-199a/214 cluster to regulate tumor survival and progression in human hepatocellular cancer. PLoS One 2012, 7, e31518.
Behrman, S.; Acosta-Alvear, D.; Walter, P. A CHOP-regulated microRNA controls rhodopsin expression. J. Cell Biol. 2011, 192, 919–927, doi:10.1083/jcb.201010055.
[53]
Deng, J.; Lu, P.D.; Zhang, Y.; Scheuner, D.; Kaufman, R.J.; Sonenberg, N.; Harding, H.P.; Ron, D. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol. Cell. Biol. 2004, 24, 10161–10168, doi:10.1128/MCB.24.23.10161-10168.2004.
[54]
Jiang, H.Y.; Wek, S.A.; McGrath, B.C.; Scheuner, D.; Kaufman, R.J.; Cavener, D.R.; Wek, R.C. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol. Cell. Biol. 2003, 23, 5651–5663, doi:10.1128/MCB.23.16.5651-5663.2003.
[55]
Romero-Ramirez, L.; Cao, H.; Nelson, D.; Hammond, E.; Lee, A.-H.; Yoshida, H.; Mori, K.; Glimcher, L.H.; Denko, N.C.; Giaccia, A.J.; et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 2004, 64, 5943–5947, doi:10.1158/0008-5472.CAN-04-1606.
[56]
Hay, R.T. SUMO: A history of modification. Mol. Cell 2005, 18, 1–12, doi:10.1016/j.molcel.2005.03.012.
[57]
Lee, A.-H.; Iwakoshi, N.N.; Anderson, K.C.; Glimcher, L.H. Proteasome inhibitors disrupt the unfolded response in myeloma cells. Proc. Natl. Acad. Sci. 2003, 100, 9946–9951.
[58]
Zhou, Y.; Lee, J.; Reno, C.M.; Sun, C.; Park, S.W.; Chung, J.; Lee, J.; Fisher, S.J.; White, M.F.; Biddinger, S.B.; et al. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat. Med. 2011, 17, 356–365, doi:10.1038/nm.2293.
[59]
Accili, D.; Arden, K.C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004, 117, 421–426, doi:10.1016/S0092-8674(04)00452-0.
[60]
Gross, D.N.; van den Heuvel, A.P.J.; Birnbaum, M.J. The role of FoxO in the regulation of metabolism. Oncogene 2008, 27, 2320–2336, doi:10.1038/onc.2008.25.
[61]
Yoshida, H.; Uemura, A.; Mori, K. pXBP1(u), a negative regulator of the unfolded protein response activator pXBP1(s), targets ATF6 but not ATF4 in proteasome-mediated degradation. Cell Struct. Funct. 2009, 34, 1–10, doi:10.1247/csf.06028.
[62]
Newman, J.R.S.; Keating, A.E. Comprehensive identification of human bZIP interactions with coiled-coil arrays. Science 2003, 300, 2097–2101, doi:10.1126/science.1084648.
[63]
Hotamisligil, G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010, 140, 900–917, doi:10.1016/j.cell.2010.02.034.
[64]
Koong, A.C.; Chauhan, V.; Romero-Ramirez, L. Targeting XBP-1 as a novel anti-cancer strategy. Cancer Biol. Ther. 2006, 5, 756–759, doi:10.4161/cbt.5.7.2973.
