The impact of the unfolded protein response on human disease

Journal of Cell Biology

Volumn 197, Issue 7, 2012, Pages 857-867

  Wang, Shiyu ^a   Kaufman, Randal J ^a  

^a BURNHAM INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; ACTIVATING TRANSCRIPTION FACTOR 6; CALNEXIN; CALRETICULIN; GLUCOSE REGULATED PROTEIN 78; GLUCOSE REGULATED PROTEIN 94; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 153; NEUROPEPTIDE Y; SELENOPROTEIN; SOMATOSTATIN; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; X BOX BINDING PROTEIN 1;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; APOPTOSIS; CELL FUNCTION; CELL SECRETION; CELL STRESS; DEGENERATIVE DISEASE; DIABETES MELLITUS; ENDOPLASMIC RETICULUM; ENTERITIS; EUKARYOTIC CELL; GLIOMA; HOMEOSTASIS; HUMAN; HUNTINGTON CHOREA; HYPERGLYCEMIA; HYPERHOMOCYSTEINEMIA; HYPERLIPIDEMIA; INFLAMMATORY DISEASE; INTRACELLULAR SIGNALING; METABOLIC DISORDER; METABOLIC STRESS; NEOPLASM; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN SYNTHESIS; REVIEW; UNFOLDED PROTEIN RESPONSE; VIRUS INFECTION; WOLFRAM SYNDROME;

ANIMALS; ENDOPLASMIC RETICULUM; HOMEOSTASIS; HUMANS; PROTEIN UNFOLDING; PROTEINS; SIGNAL TRANSDUCTION;

EUKARYOTA;

EID: 84863740827     PISSN: 00219525     EISSN: 15408140     Source Type: Journal    
DOI: 10.1083/jcb.201110131     Document Type: Review

References (153)

1. Acosta-Alvear, D., Y. Zhou, A. Blais, M. Tsikitis, N.H. Lents, C. Arias, C.J. Lennon, Y. Kluger, and B.D. Dynlacht. 2007. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell. 27:53-66. http://dx.doi.org/10.1016/j.molcel.2007.06.011
2. Aghajani, A., A. Rahimi, F. Fadai, A. Ebrahimi, H. Najmabadi, and M. Ohadi. 2006. A point mutation at the calreticulin gene core promoter conserved sequence in a case of schizophrenia. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141B:294-295. http://dx.doi.org/10.1002/ajmg .b.30300
3. Allagnat, F., F. Christulia, F. Ortis, P. Pirot, S. Lortz, S. Lenzen, D.L. Eizirik, and A.K. Cardozo. 2010. Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis. Diabetologia. 53:1120-1130. http://dx.doi.org/10.1007/s00125-010-1699-7
4. Anttonen, A.K., I. Mahjneh, R.H. Hämäläinen, C. Lagier-Tourenne, O. Kopra, L. Waris, M. Anttonen, T. Joensuu, H. Kalimo, A. Paetau, et al. 2005. The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Nat. Genet. 37:1309-1311. http://dx.doi.org/ 10.1038/ng1677
5. Auf, G., A. Jabouille, S. Guérit, R. Pineau, M. Delugin, M. Bouchecareilh, N. Magnin, A. Favereaux, M. Maitre, T. Gaiser, et al. 2010. Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc. Natl. Acad. Sci. USA. 107:15553-15558. http://dx.doi.org/10.1073/pnas.0914072107
6. Back, S.H., D. Scheuner, J. Han, B. Song, M. Ribick, J. Wang, R.D. Gildersleeve, S. Pennathur, and R.J. Kaufman. 2009. Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab. 10:13-26. http://dx.doi.org/10.1016/j.cmet.2009.06.002
7. Bailey, D., and P. O'Hare. 2007. Transmembrane bZIP transcription factors in ER stress signaling and the unfolded protein response. Antioxid. Redox Signal. 9:2305-2321. http://dx.doi.org/10.1089/ars.2007.1796
8. Basseri, S., S. Lhoták, A.M. Sharma, and R.C. Austin. 2009. The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response. J. Lipid Res. 50:2486-2501. http://dx.doi.org/10.1194/ jlr.M900216-JLR200
9. Batchvarova, N., X.Z. Wang, and D. Ron. 1995. Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153). EMBO J. 14:4654-4661.
10. Bertolotti, A., Y. Zhang, L.M. Hendershot, H.P. Harding, and D. Ron. 2000. Dynamic interaction of BiP and ER stress transducers in the unfoldedprotein response. Nat. Cell Biol. 2:326-332. http://dx.doi.org/10.1038/ 35014014
11. Bobrovnikova-Marjon, E., C. Grigoriadou, D. Pytel, F. Zhang, J. Ye, C. Koumenis, D. Cavener, and J.A. Diehl. 2010. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene. 29:3881-3895. http://dx.doi.org/10.1038/onc.2010.153
12. Boyce, M., K.F. Bryant, C. Jousse, K. Long, H.P. Harding, D. Scheuner, R.J. Kaufman, D. Ma, D.M. Coen, D. Ron, and J. Yuan. 2005. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 307:935-939. http://dx.doi.org/10.1126/science.1101902
13. Breslow, D.K., S.R. Collins, B. Bodenmiller, R. Aebersold, K. Simons, A. Shevchenko, C.S. Ejsing, and J.S. Weissman. 2010. Orm family proteins mediate sphingolipid homeostasis. Nature. 463:1048-1053. http://dx.doi.org/10.1038/nature08787
14. Cavener, D.R., S. Gupta, and B.C. McGrath. 2010. PERK in beta cell biology and insulin biogenesis. Trends Endocrinol. Metab. 21:714-721. http:// dx.doi.org/10.1016/j.tem.2010.08.005
15. Cazanave, S.C., N.A. Elmi, Y. Akazawa, S.F. Bronk, J.L. Mott, and G.J. Gores. 2010. CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am. J. Physiol. Gastrointest. Liver Physiol. 299:G236- G243. http://dx.doi.org/10.1152/ajpgi.00091.2010
16. Chen, A., I.A. Muzzio, G. Malleret, D. Bartsch, M. Verbitsky, P. Pavlidis, A.L. Yonan, S. Vronskaya, M.B. Grody, I. Cepeda, et al. 2003. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron. 39:655-669. http://dx.doi.org/10.1016/S0896-6273(03)00501-4
17. Cheng, G., Z. Feng, and B. He. 2005. Herpes simplex virus 1 infection activates the endoplasmic reticulum resident kinase PERK and mediates eIF-2alpha dephosphorylation by the gamma(1)34.5 protein. J. Virol. 79:1379-1388. http://dx.doi.org/10.1128/JVI.79.3.1379-1388.2005
18. Chu, W.S., S.K. Das, H. Wang, J.C. Chan, P. Deloukas, P. Froguel, L.J. Baier, W. Jia, M.I. McCarthy, M.C. Ng, et al. 2007. Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits. Diabetes. 56:856-862. http://dx.doi.org/10.2337/db06-1305
19. Costa-Mattioli, M., D. Gobert, H. Harding, B. Herdy, M. Azzi, M. Bruno, M. Bidinosti, C. Ben Mamou, E. Marcinkiewicz, M. Yoshida, et al. 2005. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature. 436:1166-1173. http://dx.doi.org/10.1038/nature03897
20. Costa-Mattioli, M., D. Gobert, E. Stern, K. Gamache, R. Colina, C. Cuello, W. Sossin, R. Kaufman, J. Pelletier, K. Rosenblum, et al. 2007. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to longterm synaptic plasticity and memory. Cell. 129:195-206. http://dx.doi.org/10.1016/j.cell.2007.01.050
21. Cross, B.C., P.J. Bond, P.G. Sadowski, B.K. Jha, J. Zak, J.M. Goodman, R.H. Silverman, T.A. Neubert, I.R. Baxendale, D. Ron, and H.P. Harding. 2012. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl. Acad. Sci. USA. 109:E869-E878. http://dx.doi.org/10.1073/pnas.1115623109
22. Crozat, A., P. Aman, N. Mandahl, and D. Ron. 1993. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 363:640-644. http://dx.doi.org/10.1038/363640a0
23. Cullinan, S.B., D. Zhang, M. Hannink, E. Arvisais, R.J. Kaufman, and J.A. Diehl. 2003. Nrf2 is a direct PERK substrate and effector of PERKdependent cell survival. Mol. Cell. Biol. 23:7198-7209. http://dx.doi.org/10.1128/MCB.23.20.7198-7209.2003
24. Delépine, M., M. Nicolino, T. Barrett, M. Golamaully, G.M. Lathrop, and C. Julier. 2000. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat. Genet. 25:406-409. http://dx.doi.org/10.1038/78085
25. Denzel, A., M. Molinari, C. Trigueros, J.E. Martin, S. Velmurgan, S. Brown, G. Stamp, and M.J. Owen. 2002. Early postnatal death and motor disorders in mice congenitally deficient in calnexin expression. Mol. Cell. Biol. 22:7398-7404. http://dx.doi.org/10.1128/MCB.22.21.7398-7404.2002
26. Dimopoulos, M.A., J.F. San-Miguel, and K.C. Anderson. 2011. Emerging therapies for the treatment of relapsed or refractory multiple myeloma. Eur. J. Haematol. 86:1-15. http://dx.doi.org/10.1111/j.1600-0609.2010.01542
27. Dorner, A.J., L.C. Wasley, and R.J. Kaufman. 1989. Increased synthesis of secreted proteins induces expression of glucose-regulated proteins in butyratetreated Chinese hamster ovary cells. J. Biol. Chem. 264:20602-20607.
28. Doyle, K.M., D. Kennedy, A.M. Gorman, S. Gupta, S.J. Healy, and A. Samali. 2011. Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J. Cell. Mol. Med. 15:2025-2039. http://dx.doi.org/10.1111/j.1582-4934.2011.01374.x
29. Elefteriou, F., M.D. Benson, H. Sowa, M. Starbuck, X. Liu, D. Ron, L.F. Parada, and G. Karsenty. 2006. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 4:441-451. http://dx.doi.org/10.1016/j.cmet.2006.10.010
30. Fagone, P., and S. Jackowski. 2009. Membrane phospholipid synthesis and endoplasmic reticulum function. J. Lipid Res. 50:S311-S316. http://dx.doi.org/10.1194/jlr.R800049-JLR200
31. Fels, D.R., and C. Koumenis. 2006. The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol. Ther. 5:723-728.
32. Fonseca, S.G., S. Ishigaki, C.M. Oslowski, S. Lu, K.L. Lipson, R. Ghosh, E. Hayashi, H. Ishihara, Y. Oka, M.A. Permutt, and F. Urano. 2010. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J. Clin. Invest. 120:744-755. http://dx.doi.org/10.1172/JCI39678
33. Franks, P.W., O. Rolandsson, S.L. Debenham, K.A. Fawcett, F. Payne, C. Dina, P. Froguel, K.L. Mohlke, C. Willer, T. Olsson, et al. 2008. Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations. Diabetologia. 51:458-463. http://dx.doi.org/10.1007/s00125-007-0887-6
34. Fu, S., S.M. Watkins, and G.S. Hotamisligil. 2012. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 15:623-634. http://dx.doi.org/10.1016/j.cmet.2012.03.007
35. Fujimoto, T., K. Yoshimatsu, K. Watanabe, H. Yokomizo, T. Otani, A. Matsumoto, G. Osawa, M. Onda, and K. Ogawa. 2007. Overexpression of human X-box binding protein 1 (XBP-1) in colorectal adenomas and adenocarcinomas. Anticancer Res. 27(1A):127-131.
36. Gardner, B.M., and P. Walter. 2011. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science. 333:1891-1894. http://dx.doi.org/10.1126/science.1209126
37. Ghosh, R., K.L. Lipson, K.E. Sargent, A.M. Mercurio, J.S. Hunt, D. Ron, and F. Urano. 2010. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS ONE. 5:e9575. http://dx.doi.org/10.1371/ journal.pone.0009575
38. Gow, A., and L. Wrabetz. 2009. CHOP and the endoplasmic reticulum stress response in myelinating glia. Curr. Opin. Neurobiol. 19:505-510. http:// dx.doi.org/10.1016/j.conb.2009.08.007
39. Gragnoli, C. 2008. CHOP T/C and C/T haplotypes contribute to early-onset type 2 diabetes in Italians. J. Cell. Physiol. 217:291-295. http://dx.doi.org/10.1002/jcp.21553
40. Greenman, C., P. Stephens, R. Smith, G.L. Dalgliesh, C. Hunter, G. Bignell, H. Davies, J. Teague, A. Butler, C. Stevens, et al. 2007. Patterns of somatic mutation in human cancer genomes. Nature. 446:153-158. http://dx.doi.org/10.1038/nature05610
41. Han, D., A.G. Lerner, L. Vande Walle, J.P. Upton, W. Xu, A. Hagen, B.J. Backes, S.A. Oakes, and F.R. Papa. 2009. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 138:562-575. http://dx.doi.org/10.1016/j.cell.2009.07.017
42. Harding, H.P., I. Novoa, Y. Zhang, H. Zeng, R. Wek, M. Schapira, and D. Ron. 2000a. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell. 6:1099-1108. http://dx.doi.org/10.1016/S1097-2765(00)00108-8
43. Harding, H.P., Y. Zhang, A. Bertolotti, H. Zeng, and D. Ron. 2000b. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell. 5:897-904. http://dx.doi.org/10.1016/S1097-2765(00)80330-5
44. Harding, H.P., Y. Zhang, H. Zeng, I. Novoa, P.D. Lu, M. Calfon, N. Sadri, C. Yun, B. Popko, R. Paules, et al. 2003. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell. 11:619-633. http://dx.doi.org/10.1016/S1097-2765(03)00105-9
45. Hart, K., N.E. Landvik, H. Lind, V. Skaug, A. Haugen, and S. Zienolddiny. 2011. A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer. Lung Cancer. 71:123-129. http://dx.doi.org/10.1016/j.lungcan.2010.04.016
46. Hayashi, A., T. Kasahara, K. Iwamoto, M. Ishiwata, M. Kametani, C. Kakiuchi, T. Furuichi, and T. Kato. 2007. The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development. J. Biol. Chem. 282:34525-34534. http://dx.doi.org/10.1074/jbc.M704300200
47. Hayashi, A., T. Kasahara, M. Kametani, and T. Kato. 2008. Attenuated BDNF-induced upregulation of GABAergic markers in neurons lacking Xbp1. Biochem. Biophys. Res. Commun. 376:758-763. http://dx.doi.org/10.1016/j.bbrc.2008.09.059
48. Healy, S.J., A.M. Gorman, P. Mousavi-Shafaei, S. Gupta, and A. Samali. 2009. Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur. J. Pharmacol. 625:234-246. http://dx.doi.org/10.1016/ j.ejphar.2009.06.064
49. Hetz, C.A., and C. Soto. 2006. Stressing out the ER: a role of the unfolded protein response in prion-related disorders. Curr. Mol. Med. 6:37-43. http:// dx.doi.org/10.2174/156652406775574578
50. Hetz, C., P. Thielen, S. Matus, M. Nassif, F. Court, R. Kiffin, G. Martinez, A.M. Cuervo, R.H. Brown, and L.H. Glimcher. 2009. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 23:2294-2306. http://dx.doi.org/10.1101/gad.1830709
51. Hjelmqvist, L., M. Tuson, G. Marfany, E. Herrero, S. Balcells, and R. Gonzalez-Duarte. 2002. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol. 3:RESEARCH0027. http://dx.doi.org/10.1186/gb-2002-3-6-research0027
52. Höglinger, G.U., N.M. Melhem, D.W. Dickson, P.M. Sleiman, L.S. Wang, L. Klei, R. Rademakers, R. de Silva, I. Litvan, D.E. Riley, et al; PSP Genetics Study Group. 2011. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet. 43:699-705. http://dx.doi.org/10.1038/ng.859
53. Hollien, J., J.H. Lin, H. Li, N. Stevens, P. Walter, and J.S. Weissman. 2009. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186:323-331. http://dx.doi.org/10.1083/jcb.200903014
54. Hotamisligil, G.S. 2010. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 140:900-917. http://dx.doi.org/10.1016/ j.cell.2010.02.034
55. Huang, C.J., C.Y. Lin, L. Haataja, T. Gurlo, A.E. Butler, R.A. Rizza, and P.C. Butler. 2007. High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes. 56:2016-2027. http://dx.doi.org/10.2337/db07-0197
56. Inoue, H., Y. Tanizawa, J. Wasson, P. Behn, K. Kalidas, E. Bernal-Mizrachi, M. Mueckler, H. Marshall, H. Donis-Keller, P. Crock, et al. 1998. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat. Genet. 20:143-148. http://dx.doi.org/10.1038/2441
57. Ishihara, H., S. Takeda, A. Tamura, R. Takahashi, S. Yamaguchi, D. Takei, T. Yamada, H. Inoue, H. Soga, H. Katagiri, et al. 2004. Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulussecretion coupling in insulin secretion. Hum. Mol. Genet. 13:1159-1170. http://dx.doi.org/10.1093/hmg/ddh125
58. Itoh, N., T. Sei, K. Nose, and H. Okamoto. 1978. Glucose stimulation of the proinsulin synthesis in isolated pancreatic islets without increasing amount of proinsulin mRNA. FEBS Lett. 93:343-347. http://dx.doi.org/ 10.1016/0014-5793(78)81136-3
59. Iwakoshi, N.N., M. Pypaert, and L.H. Glimcher. 2007. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J. Exp. Med. 204:2267-2275. http://dx.doi.org/10.1084/jem.20070525
60. Iwawaki, T., R. Akai, S. Yamanaka, and K. Kohno. 2009. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc. Natl. Acad. Sci. USA. 106:16657-16662. http://dx.doi.org/10.1073/pnas.0903775106
61. Ji, C., N. Kaplowitz, M.Y. Lau, E. Kao, L.M. Petrovic, and A.S. Lee. 2011. Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology. 54:229-239. http://dx.doi.org/10.1002/hep.24368
62. Kakiuchi, C., K. Iwamoto, M. Ishiwata, M. Bundo, T. Kasahara, I. Kusumi, T. Tsujita, Y. Okazaki, S. Nanko, H. Kunugi, et al. 2003a. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat. Genet. 35:171-175. http://dx.doi.org/10.1038/ng1235
63. Kakiuchi, C., K. Iwamoto, M. Ishiwata, M. Bundo, T. Kasahara, I. Kusumi, T. Tsujita, Y. Okazaki, S. Nanko, H. Kunugi, et al. 2003b. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat. Genet. 35:171-175. http://dx.doi.org/10.1038/ng1235
64. Kakiuchi, C., M. Ishiwata, T. Umekage, M. Tochigi, K. Kohda, T. Sasaki, and T. Kato. 2004. Association of the XBP1-116C/G polymorphism with schizophrenia in the Japanese population. Psychiatry Clin. Neurosci. 58:438-440. http://dx.doi.org/10.1111/j.1440-1819.2004.01280.x
65. Kakiuchi, C., M. Ishiwata, S. Nanko, H. Kunugi, Y. Minabe, K. Nakamura, N. Mori, K. Fujii, T. Umekage, M. Tochigi, et al. 2005. Functional polymorphisms of HSPA5: possible association with bipolar disorder. Biochem. Biophys. Res. Commun. 336:1136-1143. http://dx.doi.org/ 10.1016/j.bbrc.2005.08.248
66. Kakiuchi, C., M. Ishiwata, S. Nanko, H. Kunugi, Y. Minabe, K. Nakamura, N. Mori, K. Fujii, T. Umekage, M. Tochigi, et al. 2007. Association analysis of HSP90B1 with bipolar disorder. J. Hum. Genet. 52:794-803. http:// dx.doi.org/10.1007/s10038-007-0188-4
67. Kammoun, H.L., H. Chabanon, I. Hainault, S. Luquet, C. Magnan, T. Koike, P. Ferré, and F. Foufelle. 2009. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J. Clin. Invest. 119:1201-1215. http://dx.doi.org/10.1172/JCI37007
68. Karasik, A., C. O'Hara, S. Srikanta, M. Swift, J.S. Soeldner, C.R. Kahn, and R.D. Herskowitz. 1989. Genetically programmed selective islet betacell loss in diabetic subjects with Wolfram's syndrome. Diabetes Care. 12:135-138. http://dx.doi.org/10.2337/diacare.12.2.135
69. Kars, M., L. Yang, M.F. Gregor, B.S. Mohammed, T.A. Pietka, B.N. Finck, B.W. Patterson, J.D. Horton, B. Mittendorfer, G.S. Hotamisligil, and S. Klein. 2010. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 59:1899-1905. http://dx.doi.org/10.2337/db10-0308
70. Kasaikina. M.V., D.E. Fomenko, V.M. Labunskyy, S.A. Lachke, W. Qiu, J.A. Moncaster, J. Zhang, M.W. Wojnarowicz Jr., S.K. Natarajan, M. Malinouski, et al. 2011. Roles of the 15-kDa selenoprotein (Sep15) in redox homeostasis and cataract development revealed by the analysis of Sep 15 knockout mice. J. Biol. Chem. 286:33203-33212. http://dx.doi.org/10.1074/jbc.M111.259218
71. Kaser, A., A.H. Lee, A. Franke, J.N. Glickman, S. Zeissig, H. Tilg, E.E. Nieuwenhuis, D.E. Higgins, S. Schreiber, L.H. Glimcher, and R.S.Blumberg. 2008. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 134:743-756. http://dx.doi.org/10.1016/j.cell.2008.07.021
72. Kaser, A., M.B. Flak, M.F. Tomczak, and R.S. Blumberg. 2011. The unfolded protein response and its role in intestinal homeostasis and inflammation. Exp. Cell Res. 317:2772-2779. http://dx.doi.org/10.1016/j.yexcr.2011.07.008
73. Kaufman, R.J. 2002. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110:1389-1398.
74. Kaufman, R.J. 2004. Regulation of mRNA translation by protein folding in the endoplasmic reticulum. Trends Biochem. Sci. 29:152-158. http://dx.doi.org/10.1016/j.tibs.2004.01.004
75. Kaufman, R.J., D. Scheuner, M. Schröder, X. Shen, K. Lee, C.Y. Liu, and S.M. Arnold. 2002. The unfolded protein response in nutrient sensing and differentiation. Nat. Rev. Mol. Cell Biol. 3:411-421. http://dx.doi.org/10.1038/nrm829
76. Koong, A.C., V. Chauhan, and L. Romero-Ramirez. 2006. Targeting XBP-1 as a novel anti-cancer strategy. Cancer Biol. Ther. 5:756-759. http://dx.doi.org/10.4161/cbt.5.7.2973
77. Ladiges, W.C., S.E. Knoblaugh, J.F. Morton, M.J. Korth, B.L. Sopher, C.R. Baskin, A. MacAuley, A.G. Goodman, R.C. LeBoeuf, and M.G. Katze. 2005. Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes. 54:1074-1081. http://dx.doi.org/10.2337/diabetes.54.4.1074
78. Laybutt, D.R., A.M. Preston, M.C. Akerfeldt, J.G. Kench, A.K. Busch, A.V. Biankin, and T.J. Biden. 2007. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 50:752-763. http://dx.doi.org/10.1007/s00125-006-0590-z
79. Lee, A.S. 2007. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 67:3496-3499. http://dx.doi.org/10.1158/0008-5472.CAN-07-0325
80. Lee, A.H., N.N. Iwakoshi, and L.H. Glimcher. 2003. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23:7448-7459. http://dx.doi.org/ 10.1128/MCB.23.21.7448-7459.2003
81. Lee, A.H., E.F. Scapa, D.E. Cohen, and L.H. Glimcher. 2008. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science. 320:1492-1496. http://dx.doi.org/10.1126/science.1158042
82. Lee, A.H., K. Heidtman, G.S. Hotamisligil, and L.H. Glimcher. 2011. Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc. Natl. Acad. Sci. USA. 108:8885-8890. http://dx.doi.org/10.1073/pnas.1105564108
83. Lee, J.H., P. Giannikopoulos, S.A. Duncan, J. Wang, C.T. Johansen, J.D. Brown, J. Plutzky, R.A. Hegele, L.H. Glimcher, and A.H. Lee. 2011. The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat. Med. 17:812-815. http://dx.doi.org/ 10.1038/nm.2347
84. Lee, M.W., D. Chanda, J. Yang, H. Oh, S.S. Kim, Y.S. Yoon, S. Hong, K.G. Park, I.K. Lee, C.S. Choi, et al. 2010. Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH. Cell Metab. 11:331-339. http://dx.doi.org/10.1016/j.cmet.2010.02.016
85. Leonardi, R., M.W. Frank, P.D. Jackson, C.O. Rock, and S. Jackowski. 2009. Elimination of the CDP-ethanolamine pathway disrupts hepatic lipid homeostasis. J. Biol. Chem. 284:27077-27089. http://dx.doi.org/10.1074/ jbc.M109.031336
86. Lipson, K.L., S.G. Fonseca, S. Ishigaki, L.X. Nguyen, E. Foss, R. Bortell, A.A. Rossini, and F. Urano. 2006. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 4:245-254. http://dx.doi.org/10.1016/j.cmet.2006.07.007
87. Luo, S., C. Mao, B. Lee, and A.S. Lee. 2006. GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol. Cell. Biol. 26:5688-5697. http://dx.doi.org/10.1128/MCB.00779-06
88. Ma, K., K.M. Vattem, and R.C. Wek. 2002. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J. Biol. Chem. 277:18728-18735. http://dx.doi.org/10.1074/jbc.M200903200
89. Malhotra, J.D., H. Miao, K. Zhang, A. Wolfson, S. Pennathur, S.W. Pipe, and R.J. Kaufman. 2008. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc. Natl. Acad. Sci. USA. 105:18525-18530. http://dx.doi.org/10.1073/pnas.0809677105
90. Mao, C., M. Wang, B. Luo, S. Wey, D. Dong, R. Wesselschmidt, S. Rawlings, and A.S. Lee. 2010. Targeted mutation of the mouse Grp94 gene disrupts development and perturbs endoplasmic reticulum stress signaling. PLoS ONE. 5:e10852. http://dx.doi.org/10.1371/journal.pone.0010852
91. Marciniak, S.J., C.Y. Yun, S. Oyadomari, I. Novoa, Y. Zhang, R. Jungreis, K. Nagata, H.P. Harding, and D. Ron. 2004. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18:3066-3077. http://dx.doi.org/10.1101/gad.1250704
92. Martinon, F., X. Chen, A.H. Lee, and L.H. Glimcher. 2010. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11:411-418. http://dx.doi.org/10.1038/ni.1857
93. Matus, S., L.H. Glimcher, and C. Hetz. 2011. Protein folding stress in neurodegenerative diseases: a glimpse into the ER. Curr. Opin. Cell Biol. 23:239-252. http://dx.doi.org/10.1016/j.ceb.2011.01.003
94. McGovern, D.P., A. Gardet, L. Törkvist, P. Goyette, J. Essers, K.D. Taylor, B.M. Neale, R.T. Ong, C. Lagacé, C. Li, et al; NIDDK IBD Genetics Consortium. 2010. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat. Genet. 42:332-337. http://dx.doi.org/ 10.1038/ng.549
95. Meex, S.J., M.M. van Greevenbroek, T.A. Ayoubi, R. Vlietinck, J.V. van Vliet-Ostaptchouk, M.H. Hofker, V.M. Vermeulen, C.G. Schalkwijk, E.J. Feskens, J.M. Boer, et al. 2007. Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians. J. Clin. Endocrinol. Metab. 92:2720-2725. http://dx.doi.org/10.1210/jc.2006-2280
96. Meex, S.J., D. Weissglas-Volkov, C.J. van der Kallen, D.J. Thuerauf, M.M. van Greevenbroek, C.G. Schalkwijk, C.D. Stehouwer, E.J. Feskens, L. Heldens, T.A. Ayoubi, et al. 2009. The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels. Arterioscler. Thromb. Vasc. Biol. 29:1322-1327. http://dx.doi.org/10.1161/ATVBAHA.108.180240
97. Merksamer, P.I., A. Trusina, and F.R. Papa. 2008. Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions. Cell. 135:933-947. http://dx.doi.org/10.1016/j.cell.2008.10.011
98. Mimura, N., M. Fulciniti, G. Gorgun, Y.T. Tai, D. Cirstea, L. Santo, Y. Hu, C. Fabre, J. Minami, H. Ohguchi, et al. 2012. Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma. Blood. http://dx.doi.org/10.1182/blood-2011-07-366633
99. Mita, M., K. Miyake, M. Zenibayashi, Y. Hirota, T. Teranishi, K. Kouyama, K. Sakaguchi, and M. Kasuga. 2008. Association study of the effect of WFS1 polymorphisms on risk of type 2 diabetes in Japanese population. Kobe J. Med. Sci. 54:E192-E199.
100. Nawrocki, S.T., J.S. Carew, K. Dunner Jr., L.H. Boise, P.J. Chiao, P. Huang, J.L. Abbruzzese, and D.J. McConkey. 2005. Bortezomib inhibits PKRlike endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res. 65:11510-11519. http://dx.doi.org/10.1158/0008-5472.CAN-05-2394
101. Nishitoh, H., A. Matsuzawa, K. Tobiume, K. Saegusa, K. Takeda, K. Inoue, S. Hori, A. Kakizuka, and H. Ichijo. 2002. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16:1345-1355. http://dx.doi.org/10.1101/gad.992302
102. Ohoka, N., S. Yoshii, T. Hattori, K. Onozaki, and H. Hayashi. 2005. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J. 24:1243-1255. http://dx.doi.org/10.1038/sj.emboj.7600596
103. Ota, T., C. Gayet, and H.N. Ginsberg. 2008. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J. Clin. Invest. 118:316-332. http://dx.doi.org/10.1172/JCI32752
104. Oyadomari, S., A. Koizumi, K. Takeda, T. Gotoh, S. Akira, E. Araki, and M. Mori. 2002. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J. Clin. Invest. 109:525-532.
105. Ozcan, U., E. Yilmaz, L. Ozcan, M. Furuhashi, E. Vaillancourt, R.O. Smith, C.Z. Görgün, and G.S. Hotamisligil. 2006. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 313:1137-1140. http://dx.doi.org/10.1126/science.1128294
106. Papandreou, I., N.C. Denko, M. Olson, H. Van Melckebeke, S. Lust, A. Tam, D.E. Solow-Cordero, D.M. Bouley, F. Offner, M. Niwa, and A.C. Koong. 2011. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood. 117:1311-1314. http://dx.doi.org/10.1182/blood-2010-08-303099
107. Park, S.W., Y. Zhou, J. Lee, A. Lu, C. Sun, J. Chung, K. Ueki, and U. Ozcan. 2010. The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat. Med. 16:429-437. http://dx.doi.org/10.1038/nm.2099
108. Promlek, T., Y. Ishiwata-Kimata, M. Shido, M. Sakuramoto, K. Kohno, and Y. Kimata. 2011. Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways. Mol. Biol. Cell. 22:3520-3532. http://dx.doi.org/10.1091/mbc.E11-04-0295
109. Puthalakath, H., L.A. O'Reilly, P. Gunn, L. Lee, P.N. Kelly, N.D. Huntington, P.D. Hughes, E.M. Michalak, J. McKimm-Breschkin, N. Motoyama, et al. 2007. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 129:1337-1349. http://dx.doi.org/10.1016/j.cell.2007.04.027
110. Reddy, J.K., and M.S. Rao. 2006. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am. J. Physiol. Gastrointest. Liver Physiol. 290:G852-G858. http://dx.doi.org/10.1152/ajpgi.00521.2005
111. Reimold, A.M., A. Etkin, I. Clauss, A. Perkins, D.S. Friend, J. Zhang, H.F. Horton, A. Scott, S.H. Orkin, M.C. Byrne, et al. 2000. An essential role in liver development for transcription factor XBP-1. Genes Dev. 14:152-157.
112. Reimold, A.M., N.N. Iwakoshi, J. Manis, P. Vallabhajosyula, E. Szomolanyi-Tsuda, E.M. Gravallese, D. Friend, M.J. Grusby, F. Alt, and L.H. Glimcher. 2001. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 412:300-307. http://dx.doi.org/10.1038/35085509
113. Rutkowski, D.T., S.M. Arnold, C.N. Miller, J. Wu, J. Li, K.M. Gunnison, K. Mori, A.A. Sadighi Akha, D. Raden, and R.J. Kaufman. 2006. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 4:e374. http://dx.doi.org/10.1371/journal.pbio.0040374
114. Rutkowski, D.T., J. Wu, S.H. Back, M.U. Callaghan, S.P. Ferris, J. Iqbal, R. Clark, H. Miao, J.R. Hassler, J. Fornek, et al. 2008. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev. Cell. 15:829-840. http://dx.doi.org/10.1016/j.devcel.2008.10.015
115. Sammels, E., J.B. Parys, L. Missiaen, H. De Smedt, and G. Bultynck. 2010. Intracellular Ca2+ storage in health and disease: a dynamic equilibrium. Cell Calcium. 47:297-314. http://dx.doi.org/10.1016/j.ceca.2010.02.001
116. Scheuner, D., B. Song, E. McEwen, C. Liu, R. Laybutt, P. Gillespie, T. Saunders, S. Bonner-Weir, and R.J. Kaufman. 2001. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell. 7:1165-1176. http://dx.doi.org/10.1016/S1097-2765(01)00265-9
117. Scheuner, D., D. Vander Mierde, B. Song, D. Flamez, J.W. Creemers, K. Tsukamoto, M. Ribick, F.C. Schuit, and R.J. Kaufman. 2005. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat. Med. 11:757-764. http://dx.doi.org/10.1038/nm1259
118. Schewe, D.M., and J.A. Aguirre-Ghiso. 2008. ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc. Natl. Acad. Sci. USA. 105:10519-10524. http://dx.doi.org/10.1073/pnas.0800939105
119. Schindler, A.J., and R. Schekman. 2009. In vitro reconstitution of ER-stress induced ATF6 transport in COPII vesicles. Proc. Natl. Acad. Sci. USA. 106:17775-17780. http://dx.doi.org/10.1073/pnas.0910342106
120. Schröder, M., and R.J. Kaufman. 2005. The mammalian unfolded protein response. Annu. Rev. Biochem. 74:739-789. http://dx.doi.org/10.1146/ annurev.biochem.73.011303.074134
121. Schuck, S., W.A. Prinz, K.S. Thorn, C. Voss, and P. Walter. 2009. Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J. Cell Biol. 187:525-536. http://dx.doi.org/10.1083/jcb.200907074
122. Sha, H., Y. He, H. Chen, C. Wang, A. Zenno, H. Shi, X. Yang, X. Zhang, and L. Qi. 2009. The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis. Cell Metab. 9:556-564. http://dx.doi.org/10.1016/j.cmet.2009.04.009
123. Shen, J., X. Chen, L. Hendershot, and R. Prywes. 2002. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell. 3:99-111. http://dx.doi.org/10.1016/S1534-5807(02)00203-4
124. Shi, Y., K.M. Vattem, R. Sood, J. An, J. Liang, L. Stramm, and R.C. Wek. 1998. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol. Cell. Biol. 18:7499-7509.
125. Silva, R.M., V. Ries, T.F. Oo, O. Yarygina, V. Jackson-Lewis, E.J. Ryu, P.D. Lu, S.J. Marciniak, D. Ron, S. Przedborski, et al. 2005. CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J. Neurochem. 95:974-986. http://dx.doi.org/10.1111/j.1471-4159.2005.03428.x
126. Song, B., D. Scheuner, D. Ron, S. Pennathur, and R.J. Kaufman. 2008. Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J. Clin. Invest. 118:3378-3389. http://dx.doi.org/10.1172/JCI34587
127. Stutzmann, G.E., and M.P. Mattson. 2011. Endoplasmic reticulum Ca(2+) handling in excitable cells in health and disease. Pharmacol. Rev. 63:700-727. http://dx.doi.org/10.1124/pr.110.003814
128. Thameem, F., V.S. Farook, C. Bogardus, and M. Prochazka. 2006. Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes. 55:839-842. http://dx.doi.org/10.2337/diabetes.55.03.06.db05-1002
129. Thorp, E., G. Li, T.A. Seimon, G. Kuriakose, D. Ron, and I. Tabas. 2009. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metab. 9:474-481. http://dx.doi.org/10.1016/j.cmet.2009.03.003
130. Tsaytler, P., H.P. Harding, D. Ron, and A. Bertolotti. 2011. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science. 332:91-94. http://dx.doi.org/10.1126/science.1201396
131. Tyson, J.R., and C.J. Stirling. 2000. LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum. EMBO J. 19:6440-6452. http://dx.doi.org/10.1093/emboj/ 19.23.6440
132. Usui, M., S. Yamaguchi, Y. Tanji, R. Tominaga, Y. Ishigaki, M. Fukumoto, H. Katagiri, K. Mori, Y. Oka, and H. Ishihara. 2012. Atf6alpha-null mice are glucose intolerant due to pancreatic beta-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism. http:// dx.doi.org/10.1016/j.metabol.2012.01.004
133. Vecchi, C., G. Montosi, K. Zhang, I. Lamberti, S.A. Duncan, R.J. Kaufman, and A. Pietrangelo. 2009. ER stress controls iron metabolism through induction of hepcidin. Science. 325:877-880. http://dx.doi.org/10.1126/ science.1176639
134. Wang, Y., L. Vera, W.H. Fischer, and M. Montminy. 2009. The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature. 460:534-537.
135. Woo, C.W., D. Cui, J. Arellano, B. Dorweiler, H. Harding, K.A. Fitzgerald, D. Ron, and I. Tabas. 2009. Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. Nat. Cell Biol. 11:1473-1480. http://dx.doi.org/10.1038/ncb1996
136. Wu, J., D.T. Rutkowski, M. Dubois, J. Swathirajan, T. Saunders, J. Wang, B. Song, G.D. Yau, and R.J. Kaufman. 2007. ATF6alpha optimizes longterm endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell. 13:351-364. http://dx.doi.org/10.1016/j.devcel.2007.07.005
137. Xiao, C., A. Giacca, and G.F. Lewis. 2011. Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. Diabetes. 60:918-924. http://dx.doi.org/10.2337/db10-1433
138. Yamaguchi, H., and H.G. Wang. 2004. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 279:45495-45502. http://dx.doi.org/ 10.1074/jbc.M406933200
139. Yamaguchi, S., H. Ishihara, T. Yamada, A. Tamura, M. Usui, R. Tominaga, Y. Munakata, C. Satake, H. Katagiri, F. Tashiro, et al. 2008. ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress. Cell Metab. 7:269-276. http://dx.doi.org/ 10.1016/j.cmet.2008.01.008
140. Yamamoto, K., T. Sato, T. Matsui, M. Sato, T. Okada, H. Yoshida, A. Harada, and K. Mori. 2007. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev. Cell. 13:365-376. http://dx.doi.org/ 10.1016/j.devcel.2007.07.018
141. Yamamoto, K., K. Takahara, S. Oyadomari, T. Okada, T. Sato, A. Harada, and K. Mori. 2010. Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol. Biol. Cell. 21:2975-2986. http://dx.doi.org/10.1091/mbc.E09-02-0133
142. Ye, J., M. Kumanova, L.S. Hart, K. Sloane, H. Zhang, D.N. De Panis, E. Bobrovnikova-Marjon, J.A. Diehl, D. Ron, and C. Koumenis. 2010. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 29:2082-2096. http:// dx.doi.org/10.1038/emboj.2010.81
143. Ye, R., D.Y. Jung, J.Y. Jun, J. Li, S. Luo, H.J. Ko, J.K. Kim, and A.S. Lee. 2010. Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance. Diabetes. 59:6-16. http://dx.doi.org/10.2337/db09-0755
144. Yilmaz, E., R. Akar, S.T. Eker, G. Deda, Y. Adiguzel, and N. Akar. 2010. Relationship between functional promoter polymorphism in the XBP1 gene (-116C/G) and atherosclerosis, ischemic stroke and hyperhomocysteinemia. Mol. Biol. Rep. 37:269-272. http://dx.doi.org/10.1007/ s11033-009-9674-4
145. Yoshida, H., T. Matsui, A. Yamamoto, T. Okada, and K. Mori. 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. http:// dx.doi.org/10.1016/S0092-8674(01)00611-0
146. Zhang, C., G. Wang, Z. Zheng, K.R. Maddipati, X. Zhang, G. Dyson, P. Williams, S.A. Duncan, R.J. Kaufman, and K. Zhang. 2012. Endoplasmic reticulumtethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice. Hepatology. 55:1070-1082. http://dx.doi.org/10.1002/hep.24783
147. Zhang, K., H.N. Wong, B. Song, C.N. Miller, D. Scheuner, and R.J. Kaufman. 2005. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J. Clin. Invest. 115:268-281.
148. Zhang, K., X. Shen, J. Wu, K. Sakaki, T. Saunders, D.T. Rutkowski, S.H. Back, and R.J. Kaufman. 2006. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell. 124:587-599. http://dx.doi.org/10.1016/j.cell.2005.11.040
149. Zhang, K., S. Wang, J. Malhotra, J.R. Hassler, S.H. Back, G. Wang, L. Chang, W. Xu, H. Miao, R. Leonardi, et al. 2011. The unfolded protein response transducer IRE1? prevents ER stress-induced hepatic steatosis. EMBO J. 30:1357-1375. http://dx.doi.org/10.1038/emboj.2011.52
150. Zhao, L., C. Longo-Guess, B.S. Harris, J.W. Lee, and S.L. Ackerman. 2005. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat. Genet. 37:974-979. http://dx.doi.org/10.1038/ng1620
151. Zhao, L., C. Rosales, K. Seburn, D. Ron, and S.L. Ackerman. 2010. Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjögren syndrome. Hum. Mol. Genet. 19:25-35. http://dx.doi.org/10.1093/hmg/ddp464
152. Zhou, Y., J. Lee, C.M. Reno, C. Sun, S.W. Park, J. Chung, J. Lee, S.J. Fisher, M.F. White, S.B. Biddinger, and U. Ozcan. 2011. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat. Med. 17:356-365. http://dx.doi.org/10.1038/nm.2293
153. Zinszner, H., M. Kuroda, X. Wang, N. Batchvarova, R.T. Lightfoot, H. Remotti, J.L. Stevens, and D. Ron. 1998. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12:982-995. http://dx.doi.org/10.1101/gad.12.7.982