The signal transduction of unfolded protein response

Transcript

1 Chinese Bulletin of Life Sciences Vol. 20, No. 2 Apr., (2008) ( ), (unfolded protein response, UPR) Q51;R73.23 A The signal transduction of unfolded protein response LI Ming 1,2, DING Jian 1, MIAO Ze-hong 1 * (1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai , China; 2 Graduate School of Chinese Academy of Sciences, Beijing , China) Abstract: In the endoplasmic reticulum(er), secretory, transmembrane and ER-resident proteins are folded into their native conformation undergo posttranslational modifications and are finally transformed into their corresponding functional forms. Disruption of protein folding causes ER stress and activates a signaling network called the unfolded proteins response (UPR). UPR increases the biosynthesis capacity of ER chaperones and foldases, and relieves the biosynthetic burden of the secretory pathway by down-regulating expression of genes encoding secreted proteins. Defects in protein folding if not corrected timely, could lead to cell apoptosis. It has been revealed that UPR is highly activated in a variety of tumors types and could contribute to tumor survival and growth. Key words: ER stress; unfold protein response; cancer [1] (unfold protein response UPR) ATP (2006AA090304) * zhm@jding.dhs.org

2 (ERassociated degradation, ERAD) - [2] (HSP) GRP78 / (CNX/CRT) [3] GRP78 BiP( ) [4] ( ) [5] BiP HSP 70 BiP N ATP C BiP BiP DnaJ DnaJ HSP40 5 ERdi1 5 N J BiP BiP ATP C 7 BiP ATP BiP ATP ATP BiP-ATP DnaJ DnaJ- J BiP BiP-ATP DnaJ-BiP-ATP- DnaJ BiP ATP ATP (ADP) DnaJ-Bip- ADP- ADP ATP BiP- [6] BiP BiP PERK IRE1 ATF6 BiP BiP HSP70 HSP90 HSP90 3 N ATP ATP C [7] HSP70 HSP90 ATP HSP70 HSP90 UDP-G (UGGT) UGGT [8] UGGT Asn-Xaa-Ser/Thr Glc3-Man9-GlcNAc2 N- UGGT 1.2 [9] [10] [11] [12] B [13] IRE1/ERN1 PERK/PEK ATF6 PERK IRE1 ATF6

3 248 1 Bip IRE1 PERK ATF6 PERK elf2 Bip IRE1 TRAF2 ASK JIK JNK c-jun Bcl-2 XBP1 XBP1S ATF6 Bip S1P S2P UPR caspase12 caspase9 caspase3 Ca 2+ Ca 2+ CytoC IRE1 PERK BiP BiP IRE1 PERK BiP IRE1 PERK BiP IRE1 PERK BiP IRE1 PERK IRE1 PERK BiP IRE1 PERK [14] ATF6 BiP IRE1 PERK BiP ATF6 GLS1 GLS2 BiP GLS1 GLS2 BiP GLS2 ATF6 GLS1 BiP ATF6 BiP GLS1 ATF6 [15] PERK I N C 2 α (eif2α) GTP trna eif2-gtp-mettrna i PERK Met eif2α 51 eif2α GDP GTP

4 249 IRE1 I RNA IRE1α IRE1β IRE1α IRE1β [16] IRE1 BiP IRE1 RNA [17] X-box 1 (XBP1) mrna IRE1 RNA XBP1 mrna, mrna XBP1 BiP [18] ATF6 II ( N C ) N (bzip) DNA C ATF6 S1P(site-1 protease) S2P(site-2 protease) [15] PERK ATF6 IRE1 1.3 PERK ATF6 IRE1 CHOP CHOP/GADD153 (growth arrest- and DNA damage-inducible gene 153) ATF6 PERK [19] CHOP N C (bzip) CHOP [20] CHOP / [21] CHOP [22] CHOP CHOP GADD34 ERO1 (DR) 5 GADD34 2C eif2α [23] ERO1 [24] DR5 caspases [25] CHOP Bcl-2 CHOP camp (CREB) Bcl-2 [22] IRE1-TRAF2-ASK1-caspase12 IRE1 2(TRAF2) TRAF2 JNK (SAPK) (ASK1) TNF [26] ASK1 [27] TRAF2 caspase12 caspase12 caspase9 caspase3 caspase12 caspase12 [28] Ca 2+ Ca 2+ Bcl-2 Ca 2+ Bax Bak Ca 2+ Ca 2+ Bax Bak [29] Bcl-2 Ca 2+ ( ) Ca 2+ Ca 2+ Ca 2+ [30] 1.4 1/3 [31] - 1(E1) ATP E1 2(E2) E2 3(E3) E3 E2

5 250 E3 E6AP C (HECT) E2 19S [32] U-box (CHIP) HSP70 HSP90 [33] (CNX/CRT) [34] α (ER degradation enhancing α-mannosidaselike protein, EDEM) I Man9GlcNAc2- Man8GlcNAc2- EDEM Man8GlcNAc2- EDEM CNX [2, 16] BiP 1.5 PH [35] [36] 150 ( vascular endothelia growth factor VEGF) [37]? [36] UPR [35] [38] DNA [4] XBP1 [39] [23] XBP1 bzip XBP1 bzip XBP1 bzip ZF(Zhangfei, ZF) [40] ATF6 XBP1 mrna IRE1 IRE1 XBP1 mrna 26 XBP1(spliced XBP1, XBP1s) XBP1s [41] EDEM (protein disulfide isomerase, PDI) [42] Back [43] XBP1 mrna XBP1 [44] XBP1 RNA(siRNA) XBP1 XBP1 VEGF (bfgf) XBP1 [45] PS341 IRE1 XBP1 [46] XBP1 [47] IGF1/Akt [48]

6 251 Koumenis [49] PERK eif2α PERK PERK eif2α eif2α(s51a) eif2α(s51a) PERK 48h eif2α 40% [23] 2 IRE1 PERK ( ) Bortezomib(PS-341 Velcade) FDA [1] Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. Trends Cell Biol, 2004, 14 (1): 20-8 [2] Ellgaard L, Molinari M, Helenius A. Setting the standards: quality control in the secretory pathway. Science, 1999, 286 (5446): [3] Trombetta ES, Parodi AJ. Quality control and protein folding in the secretory pathway. Annu Rev Cell Dev Biol, 2003, 19: [4] Dong D, Dubeau L, Bading J, et al. Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors. Hum Gene Ther, 2004, 15 (6): [5] Misra UK, Deedwania R, Pizzo SV. Activation and crosstalk between Akt, NF-κB, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78. J Biol Chem, 2006, 281 (19): [6] Ma YI, Hendershot LM. ER chaperone functions during normal and stress conditions. J Chem Neuroanat, 2004, 28 (1-2): [7] Richter K, Buchner J. Hsp90: twist and fold. Cell, 2006, 127 (2): [8] Sousa MC, Ferrero-garcia MA, Parodi AJ. Recognition of the oligosaccharide and protein moieties of glycoproteins by the UDP-Glc:glycoprotein glucosyltransferase. Biochemistry, 1992, 31 (1): [9] Kozutsumi Y, Segal M, Normington K, et al. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature, 1988, 332 (6163): [10] Pakula TM, Laxell M, Huuskonen A, et al. The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells. J Biol Chem, 2003, 278 (45): [11] Harding HP, Zhang YH, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 1999, 397 (6716): [12] Friedlander R, Jarosch E, Urban J, et al. A regulatory link between ER-associated protein degradation and the unfoldedprotein response. Nat Cell Biol, 2000, 2 (7): [13] Iwakoshi NN, Lee AH, Vallabhajosyula P, et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol, 2003, 4 (4): [14] Liu CY, Xu Z, Kaufman RJ. Structure and intermolecular interactions of the luminal dimerization domain of human IRE1α. J Biol Chem, 2003, 278 (20): [15] Shen JS, Chen X, Hendershot L, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell, 2002, 3 (1): [16] Wang XZ, Harding HP, Zhang YH, et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J, 1998, 17 (19): [17] Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J, (12): [18] Yoshida H, Haze K, Yanagi H, et al. Identification of the cisacting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem, 1998, 273 (50): [19] Ma YJ, Brewer JW, Diehl JA, et al. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol, 2002, 318 (5):

7 252 [20] Ron D, Habener JF. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev, 1992, 6 (3): [21] Oyadomari S, koizumi A, Takeda K, et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stressmediated diabetes. J Clin Invest, 2002, 109 (4): [22] Mccullough KD, Martindale JL, Klotz LO, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by downregulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol, 2001, 21 (4): [23] Bi MX, Naczki C, Koritzinsky M, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J, 2005, 24 (19): [24] Marciniak SJ, Yun CY, Oyadomari S, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev, 2004, 18 (24): [25] Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem, 2004, 279 (44): [26] Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev, 2002, 16 (11): [27] Kadowaki H, Nishitoh H, Urano F, et al. Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death Differ, 2005, 12 (1): [28] Nakagawa T, Yuan JJ. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol, 2000, 150 (4): [29] Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca 2+ : a control point for apoptosis. Science, 2003, 300 (5616): [30] Ferrari D, Pinton P, Szabadkai G, et al. Endoplasmic reticulum, Bcl-2 and Ca 2+ handling in apoptosis. Cell Calcium, 2002, 32 (5-6): [31] Mccracken AA, Brodsky JL. Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, and ATP. J Cell Biol, 1996, 132 (3): [32] Meusser B, Hirsch C, Jarosch E, et al. ERAD: the long road to destruction. Nat Cell Biol, 2005, 7 (8): [33] Meacham GC, Patterson C, Zhang WY, et al. The Hsc70 cochaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol, 2001, 3 (1): [34] Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem, 2004, 73: [35] Feldman DE, Chauhan V, Koong AC. The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res, 2005, 3 (11): [36] Tu BP, Weissman JS. Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol, 2004, 164 (3): [37] Tamatani M, Matsuyama T, Yamaguchi A, et al. ORP150 protects against hypoxia/ischemia-induced neuronal death. Nat Med, 2001, 7 (3): [38] Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer, 2004, 4 (6): [39] Iwakoshi NN, Lee AH, Glimcher LH. The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunol Rev, 2003, 194: [40] Newman JR, Keating AE. Comprehensive identification of human bzip interactions with coiled-coil arrays. Science, 2003, 300 (5628): [41] Lee K, Tirasophon W, Shen XH, et al. IRE1-mediated unconventional mrna splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev, 2002, 16 (4): [42] Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol, 2003, 23 (21): [43] Back SH, Lee K, Vink E, et al. Cytoplasmic IRE1α -mediated XBP1 mrna splicing in the absence of nuclear processing and endoplasmic reticulum stress. J Biol Chem, 2006, 281 (27): [44] Tirosh B, Iwakoshi NN, Glimcher LH, et al. Rapid turnover of unspliced Xbp-1 as a factor that modulates the unfolded protein response. J Biol Chem, 2006, 281 (9): [45] Romero-ramirez L, Cao HΒ, Nelson D, et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res, 2004, 64 (17): [46] Lee AH, Iwakoshi NN, Anderson KC, et al. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA, 2003, 100 (17): [47] Gomez BP, Riggins RB, Shajahan AN, et al. Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines. FASEB J, 2007, 21(14): [48] Hu MC, Gong HY, Lin GH, et al. XBP-1, a key regulator of unfolded protein response, activates transcription of IGF1 and Akt phosphorylation in zebrafish embryonic cell line. Biochem Biophys Res Commun, 2007, 359 (3): [49] Koumenis C, Naczki C, Koritzinsky M, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eif2alpha. Mol Cell Biol, 2002, 22 (21):