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Current Protein & Peptide Science

Editor-in-Chief

ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Review Article

Endoplasmic Reticulum Stress Signaling Pathways: Activation and Diseases

Author(s): Zhi Zheng, Yuxi Shang, Jiahui Tao, Jun Zhang* and Bingdong Sha*

Volume 20, Issue 9, 2019

Page: [935 - 943] Pages: 9

DOI: 10.2174/1389203720666190621103145

Price: $65

Abstract

Secretory and membrane proteins are folded in the endoplasmic reticulum (ER) prior to their exit. When ER function is disturbed by exogenous and endogenous factors, such as heat shock, ultraviolet radiation, hypoxia, or hypoglycemia, the misfolded proteins may accumulate, promoting ER stress. To rescue this unfavorable situation, the unfolded protein response is activated to reduce misfolded proteins within the ER. Upon ER stress, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), RNA-dependent protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6, are activated. Here, we discuss the mechanisms of PERK and IRE1 activation and describe two working models for ER stress initiation: the BiP-dependent model and the ligand-driven model. ER stress activation has been linked to multiple diseases, including cancers, Alzheimer’s disease, and diabetes. Thus, the regulation of ER stress may provide potential therapeutic targets for these diseases.

Keywords: ER stress, unfolded protein response, activation mechanism, cancer, Alzheimer's disease, diabetes.

Graphical Abstract
[1]
Moon, H.W.; Han, H.G.; Jeon, Y.J. Protein quality control in the endoplasmic reticulum and cancer. Int. J. Mol. Sci., 2018, 19(10), E3020.
[2]
Oakes, S.A.; Papa, F.R. The role of endoplasmic reticulum stress in human pathology. Annu. Rev. Pathol., 2015, 10, 173-194.
[3]
Afroze, D.; Kumar, A. ER stress in skeletal muscle remodeling and myopathies. FEBS J., 2019, 286(2), 379-398.
[4]
Hetz, C.; Chevet, E.; Oakes, S.A. Proteostasis control by the unfolded protein response. Nat. Cell Biol., 2015, 17(7), 829-838.
[5]
Wang, M.; Kaufman, R.J. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer, 2014, 14(9), 581-597.
[6]
Rozpedek, W.; Markiewicz, L.; Diehl, J.A.; Pytel, D.; Majsterek, I. Unfolded protein response and PERK kinase as a new therapeutic target in the pathogenesis of alzheimer’s disease. Curr. Med. Chem., 2015, 22(27), 3169-3184.
[7]
So, J.S. Roles of endoplasmic reticulum stress in immune responses. Mol. Cells, 2018, 41(8), 705-716.
[8]
Chaudhari, N.; Talwar, P.; Parimisetty, A.; Lefebvre d’Hellencourt, C.; Ravanan, P. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front. Cell. Neurosci., 2014, 8, 213.
[9]
Grootjans, J.; Kaser, A.; Kaufman, R.J.; Blumberg, R.S. The unfolded protein response in immunity and inflammation. Nat. Rev. Immunol., 2016, 16(8), 469-484.
[10]
Han, J.; Song, B.; Kim, J.; Kodali, V.K.; Pottekat, A.; Wang, M.; Hassler, J.; Wang, S.; Pennathur, S.; Back, S.H.; Katze, M.G.; Kaufman, R.J. Antioxidants complement the requirement for protein chaperone function to maintain beta-cell function and glucose homeostasis. Diabetes, 2015, 64(8), 2892-2904.
[11]
Kang, K.A.; Kim, J.K.; Jeong, Y.J.; Na, S.Y.; Hyun, J.W. Dictyopteris undulata extract induces apoptosis via induction of endoplasmic reticulum stress in human colon cancer cells. J. Cancer Prev., 2014, 19(2), 118-124.
[12]
Yadav, R.K.; Chae, S.W.; Kim, H.R.; Chae, H.J. Endoplasmic reticulum stress and cancer. J. Cancer Prev., 2014, 19(2), 75-88.
[13]
Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol., 2007, 8(7), 519-529.
[14]
Walter, P.; Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science, 2011, 334(6059), 1081-1086.
[15]
Shore, G.C.; Papa, F.R.; Oakes, S.A. Signaling cell death from the endoplasmic reticulum stress response. Curr. Opin. Cell Biol., 2011, 23(2), 143-149.
[16]
Song, J.; Kim, B.C.; Nguyen, D.T.; Samidurai, M.; Choi, S.M. Levodopa (L-DOPA) attenuates endoplasmic reticulum stress response and cell death signaling through DRD2 in SH-SY5Y neuronal cells under α-synuclein-induced toxicity. Neuroscience, 2017, 358, 336-348.
[17]
Ghosh, R.; Wang, L.; Wang, E.S.; Perera, B.G.; Igbaria, A.; Morita, S.; Prado, K.; Thamsen, M.; Caswell, D.; Macias, H.; Weiberth, K.F.; Gliedt, M.J.; Alavi, M.V.; Hari, S.B.; Mitra, A.K.; Bhhatarai, B.; Schürer, S.C.; Snapp, E.L.; Gould, D.B.; German, M.S.; Backes, B.J.; Maly, D.J.; Oakes, S.A.; Papa, F.R. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell, 2014, 158(3), 534-548.
[18]
Han, D.; Lerner, A.G.; Vande Walle, L.; Upton, J.P.; Xu, W.; Hagen, A.; Backes, B.J.; Oakes, S.A.; Papa, F.R. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell, 2009, 138(3), 562-575.
[19]
Mori, K. Signalling pathways in the unfolded protein response: development from yeast to mammals. J. Biochem., 2009, 146(6), 743-750.
[20]
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(6867), 92-96.
[21]
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(7), 881-891.
[22]
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(5), 992-1003.
[23]
Shen, X.; Ellis, R.E.; Lee, K.; Liu, C.Y.; Yang, K.; Solomon, A.; Yoshida, H.; Morimoto, R.; Kurnit, D.M.; Mori, K.; Kaufman, R.J. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell, 2001, 107(7), 893-903.
[24]
Hollien, J.; Lin, J.H.; Li, H.; Stevens, N.; Walter, P.; Weissman, J.S. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol., 2009, 186(3), 323-331.
[25]
Maurel, M.; Chevet, E.; Tavernier, J.; Gerlo, S. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem. Sci., 2014, 39(5), 245-254.
[26]
Lerner, A.G.; Upton, J.P.; Praveen, P.V.; Ghosh, R.; Nakagawa, Y.; Igbaria, A.; Shen, S.; Nguyen, V.; Backes, B.J.; Heiman, M.; Heintz, N.; Greengard, P.; Hui, S.; Tang, Q.; Trusina, A.; Oakes, S.A.; Papa, F.R. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab., 2012, 16(2), 250-264.
[27]
Upton, J.P.; Wang, L.; Han, D.; Wang, E.S.; Huskey, N.E.; Lim, L.; Truitt, M.; McManus, M.T.; Ruggero, D.; Goga, A.; Papa, F.R.; Oakes, S.A. IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science, 2012, 338(6108), 818-822.
[28]
Zhou, R.; Tardivel, A.; Thorens, B.; Choi, I.; Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol., 2010, 11(2), 136-140. [http://dx.doi.org/10.1038/ni.1831]. [PMID: 20023662].
[29]
Galindo-Hernandez, O.; Cordova-Guerrero, I.; Diaz-Rubio, L.J.; Pulido-Capiz, A.; Diaz-Villanueva, J.F.; Castaneda-Sanchez, C.Y.; Serafin-Higuera, N.; Garcia-Gonzalez, V. Protein translation associated to PERK arm is a new target for regulation of metainflammation: A connection with hepatocyte cholesterol. J. Cell. Biochem., 2018.
[30]
Axten, J.M. Protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK) inhibitors: a patent review (2010-2015). Expert Opin. Ther. Pat., 2017, 27(1), 37-48.
[31]
Jennings, M.D.; Pavitt, G.D. eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation. Nature, 2010, 465(7296), 378-381.
[32]
Kim, E.; Kim, J.H.; Seo, K.; Hong, K.Y.; An, S.W.A.; Kwon, J.; Lee, S.V.; Jang, S.K. eIF2A, an initiator tRNA carrier refractory to eIF2α kinases, functions synergistically with eIF5B. Cell. Mol. Life Sci., 2018, 75(23), 4287-4300.
[33]
Jackson, R.J.; Hellen, C.U.; Pestova, T.V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol., 2010, 11(2), 113-127.
[34]
Malhotra, J.D.; Kaufman, R.J. ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harb. Perspect. Biol., 2011, 3(9), a004424.
[35]
Sidrauski, C.; Acosta-Alvear, D.; Khoutorsky, A.; Vedantham, P.; Hearn, B.R.; Li, H.; Gamache, K.; Gallagher, C.M.; Ang, K.K.; Wilson, C.; Okreglak, V.; Ashkenazi, A.; Hann, B.; Nader, K.; Arkin, M.R.; Renslo, A.R.; Sonenberg, N.; Walter, P. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife, 2013, 2, e00498.
[36]
Harding, H.P.; Novoa, I.; Zhang, Y.; Zeng, H.; Wek, R.; Schapira, M.; Ron, D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell, 2000, 6(5), 1099-1108.
[37]
Rozpedek, W.; Pytel, D.; Mucha, B.; Leszczynska, H.; Diehl, J.A.; Majsterek, I. The Role of the PERK/eIF2alpha/ATF4/CHOP Signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med., 2016, 16(6), 533-544.
[38]
Li, Y.; Guo, Y.; Tang, J.; Jiang, J.; Chen, Z. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim. Biophys. Sin. (Shanghai), 2014, 46(8), 629-640.
[39]
Zhang, P.; Sun, Q.; Zhao, C.; Ling, S.; Li, Q.; Chang, Y.Z.; Li, Y. HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4. Cell. Signal., 2014, 26(3), 556-563.
[40]
Li, Y.; Guo, Y.; Tang, J.; Jiang, J.; Chen, Z. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim. Biophys. Sin. (Shanghai), 2015, 47(2), 146-147.
[41]
Cildir, G.; Low, K.C.; Tergaonkar, V. Noncanonical NF-kappaB signaling in health and disease. Trends Mol. Med., 2016, 22(5), 414-429.
[42]
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(23), 10161-10168.
[43]
Gardner, B.M.; Pincus, D.; Gotthardt, K.; Gallagher, C.M.; Walter, P. Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb. Perspect. Biol., 2013, 5(3), a013169.
[44]
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(11), 3787-3799.
[45]
Cao, S.S.; Kaufman, R.J. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid. Redox Signal., 2014, 21(3), 396-413.
[46]
Garcia-Carbonero, N.; Li, W.; Cabeza-Morales, M.; Martinez-Useros, J.; Garcia-Foncillas, J. New hope for pancreatic ductal adenocarcinoma treatment targeting endoplasmic reticulum stress Response: A Systematic Review. Int. J. Mol. Sci., 2018, 19(9), E2468.
[47]
Masciarelli, S.; Capuano, E.; Ottone, T.; Divona, M.; De Panfilis, S.; Banella, C.; Noguera, N.I.; Picardi, A.; Fontemaggi, G.; Blandino, G.; Lo-Coco, F.; Fazi, F. Retinoic acid and arsenic trioxide sensitize acute promyelocytic leukemia cells to ER stress. Leukemia, 2018, 32(2), 285-294.
[48]
Nadanaka, S.; Okada, T.; Yoshida, H.; Mori, K. Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress. Mol. Cell. Biol., 2007, 27(3), 1027-1043.
[49]
Hagerling, C.; Casbon, A.J.; Werb, Z. Balancing the innate immune system in tumor development. Trends Cell Biol., 2015, 25(4), 214-220.
[50]
Nagelkerke, A.; Bussink, J.; Sweep, F.C.; Span, P.N. The unfolded protein response as a target for cancer therapy. Biochim. Biophys. Acta, 2014, 1846(2), 277-284.
[51]
Cao, S.S.; Kaufman, R.J. Unfolded protein response. Curr. Biol., 2012, 22(16), R622-R626.
[52]
Tay, K.H.; Luan, Q.; Croft, A.; Jiang, C.C.; Jin, L.; Zhang, X.D.; Tseng, H.Y. Sustained IRE1 and ATF6 signaling is important for survival of melanoma cells undergoing ER stress. Cell. Signal., 2014, 26(2), 287-294.
[53]
Darling, N.J.; Cook, S.J. The role of MAPK signalling pathways in the response to endoplasmic reticulum stress. Biochim. Biophys. Acta, 2014, 1843(10), 2150-2163.
[54]
Wang, P.; Li, J.; Tao, J.; Sha, B. The luminal domain of the ER stress sensor protein PERK binds misfolded proteins and thereby triggers PERK oligomerization. J. Biol. Chem., 2018, 293(11), 4110-4121.
[55]
Cui, W.; Li, J.; Ron, D.; Sha, B. The structure of the PERK kinase domain suggests the mechanism for its activation. Acta Crystallogr. D Biol. Crystallogr., 2011, 67(Pt 5), 423-428.
[56]
Wang, P.; Li, J.; Sha, B. The ER stress sensor PERK luminal domain functions as a molecular chaperone to interact with misfolded proteins. Acta Crystallogr. D Struct. Biol., 2016, 72(Pt 12), 1290-1297.
[57]
Amin-Wetzel, N.; Saunders, R.A.; Kamphuis, M.J.; Rato, C.; Preissler, S.; Harding, H.P.; Ron, D. A J-Protein co-chaperone recruits BiP to monomerize ire1 and repress the unfolded protein response. Cell, 2017, 171(7), 1625-1637.
[58]
Karagöz, G.E.; Acosta-Alvear, D.; Nguyen, H.T.; Lee, C.P.; Chu, F.; Walter, P. An unfolded protein-induced conformational switch activates mammalian IRE1. eLife, 2017, 6, 6.
[59]
Gardner, B.M.; Walter, P. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science, 2011, 333(6051), 1891-1894.
[60]
Wang, J.; Lee, J.; Liem, D.; Ping, P. HSPA5 Gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum. Gene, 2017, 618, 14-23.
[61]
Wang, M.; Kaufman, R.J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature, 2016, 529(7586), 326-335.
[62]
Moenner, M.; Pluquet, O.; Bouchecareilh, M.; Chevet, E. Integrated endoplasmic reticulum stress responses in cancer. Cancer Res., 2007, 67(22), 10631-10634.
[63]
Koumenis, C. ER stress, hypoxia tolerance and tumor progression. Curr. Mol. Med., 2006, 6(1), 55-69.
[64]
Lee, A.S.; Hendershot, L.M. ER stress and cancer. Cancer Biol. Ther., 2006, 5(7), 721-722.
[65]
Cubillos-Ruiz, J.R.; Bettigole, S.E.; Glimcher, L.H. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell, 2017, 168(4), 692-706.
[66]
Chen, X.; Iliopoulos, D.; Zhang, Q.; Tang, Q.; Greenblatt, M.B.; Hatziapostolou, M.; Lim, E.; Tam, W.L.; Ni, M.; Chen, Y.; Mai, J.; Shen, H.; Hu, D.Z.; Adoro, S.; Hu, B.; Song, M.; Tan, C.; Landis, M.D.; Ferrari, M.; Shin, S.J.; Brown, M.; Chang, J.C.; Liu, X.S.; Glimcher, L.H. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature, 2014, 508(7494), 103-107.
[67]
Bobrovnikova-Marjon, E.; Grigoriadou, C.; Pytel, D.; Zhang, F.; Ye, J.; Koumenis, C.; Cavener, D.; Diehl, J.A. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene, 2010, 29(27), 3881-3895.
[68]
Hong, S.Y.; Hagen, T. Multiple myeloma Leu167Ile (c.499C>A) mutation prevents XBP1 mRNA splicing. Br. J. Haematol., 2013, 161(6), 898-901.
[69]
Hazari, Y.M.; Bashir, A.; Haq, E.U.; Fazili, K.M. Emerging tale of UPR and cancer: an essentiality for malignancy. Tumour Biol., 2016, 37(11), 14381-14390.
[70]
Shapiro, D.J.; Livezey, M.; Yu, L.; Zheng, X.; Andruska, N.; Anticipatory, U.P.R. Activation: A protective pathway and target in cancer. Trends Endocrinol. Metab., 2016, 27(10), 731-741.
[71]
Li, X.X.; Zhang, H.S.; Xu, Y.M.; Zhang, R.J.; Chen, Y.; Fan, L.; Qin, Y.Q.; Liu, Y.; Li, M.; Fang, J. Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells. Oncogene, 2017, 36(48), 6738-6746.
[72]
Cubillos-Ruiz, J.R.; Bettigole, S.E.; Glimcher, L.H. Molecular Pathways: Immunosuppressive roles of IRE1alpha-XBP1 signaling in dendritic cells of the tumor microenvironment. Clin. Cancer Res., 2016, 22(9), 2121-2126.
[73]
Inguscio, V.; Panzarini, E.; Dini, L. Autophagy contributes to the death/survival balance in cancer photodynamic therapy. Cells, 2012, 1(3), 464-491.
[74]
Karali, E.; Bellou, S.; Stellas, D.; Klinakis, A.; Murphy, C.; Fotsis, T. VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress. Mol. Cell, 2014, 54(4), 559-572.
[75]
Schewe, D.M.; Aguirre-Ghiso, J.A. ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc. Natl. Acad. Sci. USA, 2008, 105(30), 10519-10524.
[76]
Chen, X.L.; Fu, J.P.; Shi, J.; Wan, P.; Cao, H.; Tang, Z.M. CXC195 induces apoptosis and endoplastic reticulum stress in human hepatocellular carcinoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway. Mol. Med. Rep., 2015, 12(6), 8229-8236.
[77]
Wilhelm, T.; Bick, F.; Peters, K.; Mohta, V.; Tirosh, B.; Patterson, J.B.; Kharabi-Masouleh, B.; Huber, M. Infliction of proteotoxic stresses by impairment of the unfolded protein response or proteasomal inhibition as a therapeutic strategy for mast cell leukemia. Oncotarget, 2017, 9(3), 2984-3000.
[78]
Rojas-Rivera, D.; Delvaeye, T.; Roelandt, R.; Nerinckx, W.; Augustyns, K.; Vandenabeele, P.; Bertrand, M.J.M. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ., 2017, 24(6), 1100-1110.
[79]
Axten, J.M.; Romeril, S.P.; Shu, A.; Ralph, J.; Medina, J.R.; Feng, Y.; Li, W.H.; Grant, S.W.; Heerding, D.A.; Minthorn, E.; Mencken, T.; Gaul, N.; Goetz, A.; Stanley, T.; Hassell, A.M.; Gampe, R.T.; Atkins, C.; Kumar, R. Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development. ACS Med. Chem. Lett., 2013, 4(10), 964-968.
[80]
Krishnamoorthy, J.; Rajesh, K.; Mirzajani, F.; Kesoglidou, P.; Papadakis, A.I.; Koromilas, A.E. Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications. Cell Cycle, 2014, 13(5), 801-806.
[81]
Jiang, X.; Wei, Y.; Zhang, T.; Zhang, Z.; Qiu, S.; Zhou, X.; Zhang, S. Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stressassociated gene expression in retinal pigment epithelial cells. Mol. Med. Rep., 2017, 15(5), 3105-3110.
[82]
García-González, P.; Cabral-Miranda, F.; Hetz, C.; Osorio, F. Interplay between the unfolded protein response and immune function in the development of neurodegenerative diseases. Front. Immunol., 2018, 9, 2541.
[83]
Smith, H.L.; Mallucci, G.R. The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain, 2016, 139(Pt 8), 2113-2121.
[84]
Rahman, S.; Jan, A.T.; Ayyagari, A.; Kim, J.; Kim, J.; Minakshi, R. Entanglement of UPRER in Aging driven neurodegenerative diseases. Front. Aging Neurosci., 2017, 9, 341.
[85]
Roussel, B.D.; Kruppa, A.J.; Miranda, E.; Crowther, D.C.; Lomas, D.A.; Marciniak, S.J. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol., 2013, 12(1), 105-118.
[86]
Remondelli, P.; Renna, M. The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance. Front. Mol. Neurosci., 2017, 10, 187.
[87]
Nisbet, R.M.; Polanco, J.C.; Ittner, L.M.; Götz, J. Tau aggregation and its interplay with amyloid-β. Acta Neuropathol., 2015, 129(2), 207-220.
[88]
Rajmohan, R.; Reddy, P.H. Amyloid-Beta and phosphorylated tau accumulations cause abnormalities at synapses of alzheimer’s disease neurons. J. Alzheimers Dis., 2017, 57(4), 975-999.
[89]
Fan, B.; Sun, Y.J.; Liu, S.Y.; Che, L.; Li, G.Y. Neuroprotective Strategy in retinal degeneration: suppressing ER stress-induced cell death via inhibition of the mTOR Signal. Int. J. Mol. Sci., 2017, 18(1), E201.
[90]
Devi, L.; Ohno, M. PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer’s disease. Neurobiol. Aging, 2014, 35(10), 2272-2281.
[91]
Hashimoto, S.; Ishii, A.; Kamano, N.; Watamura, N.; Saito, T.; Ohshima, T.; Yokosuka, M.; Saido, T.C. Endoplasmic reticulum stress responses in mouse models of Alzheimer’s disease: Overexpression paradigm versus knockin paradigm. J. Biol. Chem., 2018, 293(9), 3118-3125.
[92]
Gitler, A.D.; Dhillon, P.; Shorter, J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis. Model. Mech., 2017, 10(5), 499-502.
[93]
Cornejo, V.H.; Hetz, C. The unfolded protein response in Alzheimer’s disease. Semin. Immunopathol., 2013, 35(3), 277-292.
[94]
Ma, T.; Trinh, M.A.; Wexler, A.J.; Bourbon, C.; Gatti, E.; Pierre, P.; Cavener, D.R.; Klann, E. Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat. Neurosci., 2013, 16(9), 1299-1305.
[95]
Ohno, M. Roles of eIF2α kinases in the pathogenesis of Alzheimer’s disease. Front. Mol. Neurosci., 2014, 7, 22.
[96]
Halliday, M.; Radford, H.; Zents, K.A.M.; Molloy, C.; Moreno, J.A.; Verity, N.C.; Smith, E.; Ortori, C.A.; Barrett, D.A.; Bushell, M.; Mallucci, G.R. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain, 2017, 140(6), 1768-1783.
[97]
Halliday, M.; Mallucci, G.R. Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory. Neuropathol. Appl. Neurobiol., 2015, 41(4), 414-427.
[98]
Scheper, W.; Hoozemans, J.J. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol., 2015, 130(3), 315-331.
[99]
Radford, H.; Moreno, J.A.; Verity, N.; Halliday, M.; Mallucci, G.R. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol., 2015, 130(5), 633-642.
[100]
Marré, M.L.; Profozich, J.L.; Coneybeer, J.T.; Geng, X.; Bertera, S.; Ford, M.J.; Trucco, M.; Piganelli, J.D. Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes. J. Autoimmun., 2016, 72, 33-46.
[101]
Arunagiri, A.; Haataja, L.; Cunningham, C.N.; Shrestha, N.; Tsai, B.; Qi, L.; Liu, M.; Arvan, P. Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes. Ann. N. Y. Acad. Sci., 2018, 1418(1), 5-19.
[102]
Wang, R.; Munoz, E.E.; Zhu, S.; McGrath, B.C.; Cavener, D.R. Perk gene dosage regulates glucose homeostasis by modulating pancreatic β-cell functions. PLoS One, 2014, 9(6), e99684.
[103]
Ariyasu, D.; Yoshida, H.; Hasegawa, Y. Endoplasmic reticulum (ER) stress and endocrine disorders. Int. J. Mol. Sci., 2017, 18(2), E382.
[104]
Sowers, C.R.; Wang, R.; Bourne, R.A.; McGrath, B.C.; Hu, J.; Bevilacqua, S.C.; Paton, J.C.; Paton, A.W.; Collardeau-Frachon, S.; Nicolino, M.; Cavener, D.R. The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones. J. Biol. Chem., 2018, 293(14), 5134-5149. [http://dx.doi.org/10.1074/jbc.M117.813790]. [PMID: 29444822].
[105]
Wang, R.; McGrath, B.C.; Kopp, R.F.; Roe, M.W.; Tang, X.; Chen, G.; Cavener, D.R. Insulin secretion and Ca2+ dynamics in β-cells are regulated by PERK (EIF2AK3) in concert with calcineurin. J. Biol. Chem., 2013, 288(47), 33824-33836.
[106]
Gupta, S.; McGrath, B.; Cavener, D.R. PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes, 2010, 59(8), 1937-1947.
[107]
Kefalas, G.; Larose, L. PERK leads a hub dictating pancreatic β cell homoeostasis. Biol. Cell, 2018, 110(2), 27-32.
[108]
Al-Sinani, S.; Al-Yaarubi, S.; Sharef, S.W.; Al-Murshedi, F.; Al-Maamari, W. Novel mutation in wolcott-rallison syndrome with variable expression in two omani siblings. Oman Med. J., 2015, 30(2), 138-141.
[109]
Szabat, M.; Page, M.M.; Panzhinskiy, E.; Skovsø, S.; Mojibian, M.; Fernandez-Tajes, J.; Bruin, J.E.; Bround, M.J.; Lee, J.T.; Xu, E.E.; Taghizadeh, F.; O’Dwyer, S.; van de Bunt, M.; Moon, K.M.; Sinha, S.; Han, J.; Fan, Y.; Lynn, F.C.; Trucco, M.; Borchers, C.H.; Foster, L.J.; Nislow, C.; Kieffer, T.J.; Johnson, J.D. Reduced Insulin production relieves endoplasmic reticulum stress and induces beta cell proliferation. Cell Metab., 2016, 23(1), 179-193.
[110]
Hiraoka, H.; Nakahara, K.; Kaneko, Y.; Akiyama, S.; Okuda, K.; Iwawaki, T.; Fujimura, M.; Kumagai, Y.; Takasugi, N.; Uehara, T. Modulation of unfolded protein response by methylmercury. Biol. Pharm. Bull., 2017, 40(9), 1595-1598.
[111]
Usui, M.; Yamaguchi, S.; Tanji, Y.; Tominaga, R.; Ishigaki, Y.; Fukumoto, M.; Katagiri, H.; Mori, K.; Oka, Y.; Ishihara, H. Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism, 2012, 61(8), 1118-1128.
[112]
Nozaki, Ji.; Kubota, H.; Yoshida, H.; Naitoh, M.; Goji, J.; Yoshinaga, T.; Mori, K.; Koizumi, A.; Nagata, K. The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2+/Akita pancreatic beta cells. Genes Cells, 2004, 9(3), 261-270.

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