Extracellular/intracellular stimuli can influence eukaryotic cell function through organelles that regulate critical signaling pathways. The endoplasmic reticulum (ER), for example, impacts cellular processes including protein synthesis, folding and secretion; amino acid transport; apoptosis; cell proliferation; lipid synthesis across major cell types in response to stimuli such as accumulation of misfolded proteins and glucose deprivation. Dysregulated signaling pathways underlying the ER-mediated processes mentioned above have been linked to disease conditions such as diabetes, obesity, and Alzheimer's disease. Our current understanding, however, lacks a detailed network view that integrates organelle-mediated pathway dysregulation with cellular processes and disease pathogenesis. In this report, we introduce an integrative network biology approach that combines ER-stress response pathways with basic cellular processes using data from peer-reviewed literature. As an example, we apply our systems biology approach to study the role of ER stress in pancreatic β cells under obese diabetic conditions, generate testable hypotheses, and provide novel insights into β-cell pathogenesis. 1. Introduction The endoplasmic reticulum (ER) is a 3D network of tubules and cisternae divided into the nuclear envelope, rough ER, and smooth ER, each with a distinct function. The ER performs numerous cellular functions including synthesis of secreted and membrane proteins, biosynthesis of phospholipids, cholesterol, and steroids, and degradation of glycogen and calcium homeostasis. Factors such as oxidative stress, ischemia, and increased load of nascent or misfolded proteins or perturbations in calcium homeostasis can interfere with normal ER function leading to an accumulation of misfolded proteins [1]. This process is called “ER stress” and activates the unfolding protein response (UPR), which (a) helps restore normal cellular function by stopping protein translation, and (b) activates signaling pathways to increase production of molecular chaperones involved in protein folding [2]. If the disruption is prolonged, the UPR tries to turn on the apoptotic pathway [2]. Thus, the UPR safeguards protein synthesis, posttranslational modifications, folding and secretion, calcium storage and signaling, and lipid biosynthesis. Stresses that trigger UPR include elevated secretory protein synthesis; overexpression and/or accumulation of mutant proteins [3]; aberrant Ca2+ regulation [4]; hypoxia [5]; altered glycosylation [6]; ischemia [7]; viral infections [8]; redox state of ER
References
[1]
O. Baumann and B. Walz, “Endoplasmic reticulum of animal cells and its organization into structural and functional domains,” International Review of Cytology, vol. 205, pp. 149–214, 2001.
[2]
D. Ron and P. Walter, “Signal integration in the endoplasmic reticulum unfolded protein response,” Nature Reviews Molecular Cell Biology, vol. 8, no. 7, pp. 519–529, 2007.
[3]
I. K？llner, B. Sodeik, S. Schreek et al., “Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response,” Blood, vol. 108, no. 2, pp. 493–500, 2006.
[4]
N. Dejeans, N. Tajeddine, R. Beck et al., “Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells,” Biochemical Pharmacology, vol. 79, no. 9, pp. 1221–1230, 2010.
[5]
H. Mujcic, T. Rzymski, K. M. Rouschop et al., “Hypoxic activation of the unfolded protein response (UPR) induces expression of the metastasis-associated gene LAMP3,” Radiotherapy and Oncology, vol. 92, no. 3, pp. 450–459, 2009.
[6]
R. Chapman, C. Sidrauski, and P. Walter, “Intracellular signaling from the endoplasmic reticulum to the nucleus,” Annual Review of Cell and Developmental Biology, vol. 14, pp. 459–485, 1998.
[7]
D. J. DeGracia and H. L. Montie, “Cerebral ischemia and the unfolded protein response,” Journal of Neurochemistry, vol. 91, no. 1, pp. 1–8, 2004.
[8]
G. R. Medigeshi, A. M. Lancaster, A. J. Hirsch et al., “West nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis,” Journal of Virology, vol. 81, no. 20, pp. 10849–10860, 2007.
[9]
G. G. Lavery, E. A. Walker, N. Turan et al., “Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy,” Journal of Biological Chemistry, vol. 283, no. 13, pp. 8453–8461, 2008.
[10]
Q. Li, Z. Liu, J. Guo et al., “Cholesterol overloading leads to hepatic L02 cell damage through activation of the unfolded protein response,” International Journal of Molecular Medicine, vol. 24, no. 4, pp. 459–464, 2009.
[11]
H. R. Park, A. Tomida, S. Sato et al., “Effect on tumor cells of blocking survival response to glucose deprivation,” Journal of the National Cancer Institute, vol. 96, no. 17, pp. 1300–1310, 2004.
[12]
K. L. Lipson, S. G. Fonseca, S. Ishigaki et al., “Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1,” Cell Metabolism, vol. 4, no. 3, pp. 245–254, 2006.
[13]
R. J. Kaufman, S. H. Back, B. Song, J. Han, and J. Hassler, “The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β-cells,” Diabetes, Obesity and Metabolism, vol. 12, no. 2, pp. 99–107, 2010.
[14]
S. Oyadomari, K. Takeda, M. Takiguchi et al., “Nitric oxide-induced apoptosis in pancreatic β cells is mediated by the endoplasmic reticulum stress pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 19, pp. 10845–10850, 2001.
[15]
S. Oyadomari, A. Koizumi, K. Takeda et al., “Targeted disruption of the chop gene delays endoplasmic reticulum stress-mediated diabetes,” Journal of Clinical Investigation, vol. 109, no. 4, pp. 525–532, 2002.
[16]
B. Qian, H. Wang, X. Men, et al., “TRIB3 is implicated in glucotoxicity-and endoplasmic reticulum-stress-induced beta-cell apoptosis,” Journal of Endocrinology, vol. 199, no. 3, pp. 407–416, 2008.
[17]
P. Marchetti, M. Bugliani, R. Lupi et al., “The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients,” Diabetologia, vol. 50, no. 12, pp. 2486–2494, 2007.
[18]
S. J. Marciniak, C. Y. Yun, S. Oyadomari et al., “CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum,” Genes & Development, vol. 18, no. 24, pp. 3066–3077, 2004.
[19]
M. C. ？kerfeldt, J. Howes, J. Y. Chan et al., “Cytokine-induced β-cell death is independent of endoplasmic reticulum stress signaling,” Diabetes, vol. 57, no. 11, pp. 3034–3044, 2008.
[20]
S. Del Prato, P. Marchetti, and R. C. Bonadonna, “Phasic insulin release and metabolic regulation in type 2 diabetes,” Diabetes, vol. 51, supplement 1, pp. S109–S116, 2002.
[21]
S. Del Prato and P. Marchetti, “Beta-and alpha-cell dysfunction in type 2 diabetes,” Hormone and Metabolic Research, vol. 36, no. 11-12, pp. 775–781, 2004.
[22]
D. T. Rutkowski and R. J. Kaufman, “A trip to the ER: coping with stress,” Trends in Cell Biology, vol. 14, no. 1, pp. 20–28, 2004.
[23]
R. J. Kaufman, “Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls,” Genes & Development, vol. 13, no. 10, pp. 1211–1233, 1999.
[24]
H. P. Harding, Y. Zhang, and D. Ron, “Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase,” Nature, vol. 397, no. 6716, pp. 271–274, 1999.
[25]
J. Hollien, J. H. Lin, H. Li, N. Stevens, P. Walter, and J. S. Weissman, “Regulated Ire1-dependent decay of messenger RNAs in mammalian cells,” Journal of Cell Biology, vol. 186, no. 3, pp. 323–331, 2009.
[26]
S. W. Kang, N. S. Rane, S. J. Kim, J. L. Garrison, J. Taunton, and R. S. Hegde, “Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway,” Cell, vol. 127, no. 5, pp. 999–1013, 2006.
[27]
H. P. Harding, Y. Zhang, H. Zeng et al., “An integrated stress response regulates amino acid metabolism and resistance to oxidative stress,” Molecular Cell, vol. 11, no. 3, pp. 619–633, 2003.
[28]
S. B. Cullinan and J. A. Diehl, “Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway,” International Journal of Biochemistry & Cell Biology, vol. 38, no. 3, pp. 317–332, 2006.
[29]
S. B. Cullinan, D. Zhang, M. Hannink, E. Arvisais, R. J. Kaufman, and J. A. Diehl, “Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival,” Molecular and Cellular Biology, vol. 23, no. 20, pp. 7198–7209, 2003.
[30]
S. B. Cullinan and J. A. Diehl, “PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress,” Journal of Biological Chemistry, vol. 279, no. 19, pp. 20108–20117, 2004.
[31]
H. Bommiasamy, S. H. Back, P. Fagone et al., “ATF6α induces XBP1-independent expansion of the endoplasmic reticulum,” Journal of Cell Science, vol. 122, no. 10, pp. 1626–1636, 2009.
[32]
R. Sriburi, S. Jackowski, K. Mori, and J. W. Brewer, “XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum,” Journal of Cell Biology, vol. 167, no. 1, pp. 35–41, 2004.
[33]
D. Ron and R. Y. Hampton, “Membrane biogenesis and the unfolded protein response,” Journal of Cell Biology, vol. 167, no. 1, pp. 23–25, 2004.
[34]
E. Szegezdi, S. E. Logue, A. M. Gorman, and A. Samali, “Mediators of endoplasmic reticulum stress-induced apoptosis,” EMBO Reports, vol. 7, no. 9, pp. 880–885, 2006.
[35]
M. Matsumoto, M. Minami, K. Takeda, Y. Sakao, and S. Akira, “Ectopic expression of CHOP (GADD153) induces apoptosis in M1 myeloblastic leukemia cells,” FEBS Letters, vol. 395, no. 2-3, pp. 143–147, 1996.
[36]
H. Nishitoh, A. Matsuzawa, K. Tobiume et al., “ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats,” Genes & Development, vol. 16, no. 11, pp. 1345–1355, 2002.
[37]
X. Z. Wang and D. Ron, “Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase,” Science, vol. 272, no. 5266, pp. 1347–1349, 1996.
[38]
S. M. Clee, S. T. Nadler, and A. D. Attie, “Genetic and genomic studies of the BTBR ob/ob mouse model of type 2 diabetes,” American Journal of Therapeutics, vol. 12, no. 6, pp. 491–498, 2005.
[39]
M. P. Keller, Y. Choi, P. Wang et al., “A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility,” Genome Research, vol. 18, no. 5, pp. 706–716, 2008.
[40]
T. Ranheim, C. Dumke, K. L. Schueler, G. D. Cartee, and A. D. Attie, “Interaction between BTBR and C57BL/6J genomes produces an insulin resistance syndrome in (BTBR x C57BL/6J) F1 mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 17, no. 11, pp. 3286–3293, 1997.
[41]
J. P. Stoehr, S. T. Nadler, K. L. Schueler et al., “Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci,” Diabetes, vol. 49, no. 11, pp. 1946–1954, 2000.
[42]
G. C. Weir and S. Bonner-Weir, “Five of stages of evolving β-cell dysfunction during progression to diabetes,” Diabetes, vol. 53, supplement 3, pp. S16–S21, 2004.
[43]
J. Averous, A. Bruhat, C. Jousse, V. Carraro, G. Thiel, and P. Fafournoux, “Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation,” Journal of Biological Chemistry, vol. 279, no. 7, pp. 5288–5297, 2004.
[44]
S. Gottesman, S. Wickner, and M. R. Maurizi, “Protein quality control: triage by chaperones and proteases,” Genes & Development, vol. 11, no. 7, pp. 815–823, 1997.
[45]
Y. Shen and L. M. Hendershot, “ERdj3, a stress-inducible endoplasmic reticulum dnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates,” Molecular Biology of the Cell, vol. 16, no. 1, pp. 40–50, 2005.
[46]
S. F. G？thel and M. A. Marahiel, “Peptidyl-prolyl cis-trams isomerases, a superfamily of ubiquitous folding catalysts,” Cellular and Molecular Life Sciences, vol. 55, no. 3, pp. 423–436, 1999.
[47]
G. Kozlov, P. M？？tt？nen, D. Y. Thomas, and K. Gehring, “A structural overview of the PDI family of proteins,” FEBS Journal, vol. 277, no. 19, pp. 3924–3936, 2010.
[48]
B. Knoblach, B. O. Keller, J. Groenendyk et al., “ERp19 and ERp46, new members of the thioredoxin family of endoplasmic reticulum proteins,” Molecular & Cellular Proteomics, vol. 2, no. 10, pp. 1104–1119, 2003.
[49]
R. Sriburi, S. Jackowski, K. Mori, and J. W. Brewer, “XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum,” Journal of Cell Biology, vol. 167, no. 1, pp. 35–41, 2004.
[50]
E. Karaskov, C. Scott, L. Zhang, T. Teodoro, M. Ravazzola, and A. Volchuk, “Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic β-cell apoptosis,” Endocrinology, vol. 147, no. 7, pp. 3398–3407, 2006.
[51]
A. Finka, R. U. Mattoo, and P. Goloubinoff, “Meta-analysis of heat-and chemically upregulated chaperone genes in plant and human cells,” Cell Stress and Chaperones, vol. 16, no. 1, pp. 15–31, 2011.
[52]
M. Prentki and C. J. Nolan, “Islet β cell failure in type 2 diabetes,” Journal of Clinical Investigation, vol. 116, no. 7, pp. 1802–1812, 2006.
[53]
E. Zito, K. T. Chin, J. Blais, H. P. Harding, and D. Ron, “ERO1-β, a pancreas-specific disulfide oxidase, promotes insulin biogenesis and glucose homeostasis,” Journal of Cell Biology, vol. 188, no. 6, pp. 821–832, 2010.
