Skip to main content
SpringerLink
Log in

Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The endoplasmic reticulum (ER) lumen is chemically complex and crowded with polypeptides in different stages of assembly. ER quality control monitors chaperone-assisted protein folding, stochastic errors and off-pathway intermediates. In acute conditions, potentially toxic polypeptides overflow the capacity of the chaperone system and lead to ER stress. Activation of the unfolded protein response (UPR) following ER stress buys time for non-native polypeptides to refold or be eliminated; otherwise cell death occurs. The clearance routes for deleterious proteins are endoplasmic reticulum-associated degradation (ERAD) and ER stress-activated autophagy. The ERAD pathway is a chaperone and proteasome-mediated polypeptide degradation, while autophagy applies to wider range of substances. ER stress signal transduction recruits diverse molecules and pathways upon UPR induction to compensate stress condition. NF-E2-related factor 1 (Nrf1) and Nrf2 are two transcription factors mostly known by their induction through an antioxidant response; they can also be activated by UPR machinery. Discovery of diverse molecules downstream of Nrf1 and Nrf2 has expanded our understanding of the biological impacts of these transcription factors beyond classic antioxidant activation. In this review, we summarize our current understanding of mutual relationships between Nrf1, Nrf2, and ER stress clearance mechanisms and highlight the crosstalk of specific molecules mediating these correlations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Berridge MJ (2002) The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32:235–249

    PubMed  CAS  Google Scholar 

  2. Görlach A, Klappa P, Kietzmann T (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal 8:1391–1418

    PubMed  Google Scholar 

  3. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    PubMed  CAS  Google Scholar 

  4. Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030

    PubMed  CAS  Google Scholar 

  5. Shim S, Lee W, Chung H, Jung YK (2011) Amyloid β-induced FOXRED2 mediates neuronal cell death via inhibition of proteasome activity. Cell Mol Life Sci 68:2115–2127

    PubMed  CAS  Google Scholar 

  6. Bernard-Marissal N, Moumen A, Sunyach C, Pellegrino C, Dudley K, Henderson CE, Raoul C, Pettmann B (2012) Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS. J Neurosci 32:4901–4912

    PubMed  CAS  Google Scholar 

  7. Ansari N, Khodagholi F (2012) Molecular mechanism aspect of ER stress in Alzheimer’s disease: current approaches and future strategies. Curr Drug Targ 14:114–122

    Google Scholar 

  8. Verfaillie T, Salazar M, Velasco G, Agostinis P (2010) Linking ER stress to autophagy: potential implications for cancer therapy. Int J Cell Biol 2010:930509

    PubMed  Google Scholar 

  9. Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J (1988) The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332:462–464

    PubMed  CAS  Google Scholar 

  10. Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101:249–258

    PubMed  CAS  Google Scholar 

  11. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666

    PubMed  CAS  Google Scholar 

  12. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K (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

    PubMed  CAS  Google Scholar 

  13. Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, Song B, Yau GD, Kaufman RJ (2007) ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 13:351–364

    PubMed  CAS  Google Scholar 

  14. Wong E, Cuervo AM (2010) Integration of clearance mechanisms: the proteasome and autophagy. Cold Spring Harb Perspect Biol 2:a006734

    PubMed  CAS  Google Scholar 

  15. Kroeger H, Chiang WC, Lin JH (2012) Endoplasmic reticulum-associated degradation (ERAD) of misfolded glycoproteins and mutant P23H rhodopsin in photoreceptor cells. Adv Exp Med Biol 723:559–565

    PubMed  CAS  Google Scholar 

  16. Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9:944–957

    PubMed  CAS  Google Scholar 

  17. Schröder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    PubMed  Google Scholar 

  18. Brodsky JL, McCracken AA (1999) ER protein quality control and proteasome-mediated protein degradation. Semin Cell Dev Biol 10:507–513

    PubMed  CAS  Google Scholar 

  19. Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428

    PubMed  CAS  Google Scholar 

  20. Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381

    PubMed  CAS  Google Scholar 

  21. Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293

    PubMed  CAS  Google Scholar 

  22. Pyo JO, Nah J, Jung YK (2012) Molecules and their functions in autophagy. Exp Mol Med 44:73–80

    PubMed  CAS  Google Scholar 

  23. Rafatian G, Khodagholi F, Farimani MM, Abraki SB, Gardaneh M (2012) Increase of autophagy and attenuation of apoptosis by Salvigenin promote survival of SH-SY5Y cells following treatment with H2O2. Mol Cell Biochem 371:9–22

    PubMed  CAS  Google Scholar 

  24. Ding WX, Yin XM (2008) Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy 4:141–150

    PubMed  CAS  Google Scholar 

  25. Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C, Hayashi YK, Momoi T (2007) Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet 16:618–629

    PubMed  CAS  Google Scholar 

  26. Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171:603–614

    PubMed  Google Scholar 

  27. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149–1163

    PubMed  CAS  Google Scholar 

  28. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889

    PubMed  CAS  Google Scholar 

  29. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231

    PubMed  CAS  Google Scholar 

  30. Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R, Martinez G, Cuervo AM, Brown RH, Glimcher LH (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294–2306

    PubMed  CAS  Google Scholar 

  31. Lee H, Noh JY, Oh Y, Kim Y, Chang JW, Chung CW, Lee ST, Kim M, Ryu H, Jung YK (2012) IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux. Hum Mol Genet 21:101–114

    PubMed  Google Scholar 

  32. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T (2007) ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 14:230–239

    PubMed  CAS  Google Scholar 

  33. Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24:10161–10168

    PubMed  CAS  Google Scholar 

  34. Kaneko M, Niinuma Y, Nomura Y (2003) Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull 26:931–935

    PubMed  CAS  Google Scholar 

  35. Sykiotis GP, Bohmann D (2010) Stress-activated cap’n’collar transcription factors in aging and human disease. Sci Signal 3:re3

    Google Scholar 

  36. Nguyen T, Sherratt PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43:233–260

    PubMed  CAS  Google Scholar 

  37. Venugopal R, Jaiswal AK (1998) Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17:3145–3156

    PubMed  CAS  Google Scholar 

  38. Derjuga A, Gourley TS, Holm TM, Heng HH, Shivdasani RA, Ahmed R, Andrews NC, Blank V (2004) Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus. Mol Cell Biol 24:3286–3294

    PubMed  CAS  Google Scholar 

  39. Motohashi H, O’Connor T, Katsuoka F, Engel JD, Yamamoto M (2002) Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene 294:1–12

    PubMed  CAS  Google Scholar 

  40. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322

    PubMed  CAS  Google Scholar 

  41. Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes JD, Yamamoto M (2008) Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes. J Biol Chem 283:33554–33562

    PubMed  CAS  Google Scholar 

  42. Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426

    PubMed  CAS  Google Scholar 

  43. Hertel M, Braun S, Durka S, Alzheimer C, Werner S (2002) Upregulation and activation of the Nrf-1 transcription factor in the lesioned hippocampus. Eur J Neurosci 15:1707–1711

    PubMed  Google Scholar 

  44. Cuadrado A, Moreno-Murciano P, Pedraza-Chaverri J (2009) The transcription factor Nrf2 as a new therapeutic target in Parkinson’s disease. Expert Opin Ther Targ 13:319–329

    CAS  Google Scholar 

  45. Tusi SK, Khalaj L, Ashabi G, Kiaei M, Khodagholi F (2011) Alginate oligosaccharide protects against endoplasmic reticulum- and mitochondrial-mediated apoptotic cell death and oxidative stress. Biomaterials 32:5438–5458

    PubMed  CAS  Google Scholar 

  46. Ashabi G, Alamdary SZ, Ramin M, Khodagholi F (2013) Reduction of hippocampal apoptosis by intracerebroventricular administration of extracellular signal-regulated protein kinase and/or p38 inhibitors in amyloid beta rat model of Alzheimer’s disease: involvement of nuclear-related factor-2 and nuclear factor-κB. Basic Clin Pharmacol Toxicol 112:145–155

    Google Scholar 

  47. Yang L, Calingasan NY, Thomas B, Chaturvedi RK, Kiaei M, Wille EJ, Liby KT, Williams C, Royce D, Risingsong R, Musiek ES, Morrow JD, Sporn M, Beal MF (2009) Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2 mediated transcription. PLoS ONE 4:e5757

    PubMed  Google Scholar 

  48. Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, Liby KT, Risingsong R, Sporn M, Beal MF, Kiaei M (2011) Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med 51:88–96

    PubMed  CAS  Google Scholar 

  49. Jeon WK, Hong HY, Kim BC (2011) Genipin up-regulates heme oxygenase-1 via PI3-kinase-JNK1/2-Nrf2 signaling pathway to enhance the anti-inflammatory capacity in RAW264.7 macrophages. Arch Biochem Biophys 512:119–125

    PubMed  CAS  Google Scholar 

  50. Leung L, Kwong M, Hou S, Lee C, Chan JY (2003) Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem 278:48021–48029

    PubMed  CAS  Google Scholar 

  51. Kwak MK, Itoh K, Yamamoto M, Kensler TW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22:2883–2892

    PubMed  CAS  Google Scholar 

  52. Wang W, Kwok AM, Chan JY (2007) The p65 isoform of Nrf1 is a dominant negative inhibitor of ARE-mediated transcription. J Biol Chem 282:24670–24678

    PubMed  CAS  Google Scholar 

  53. Narayanan K, Ramachandran A, Peterson MC, Hao J, Kolstø AB, Friedman AD, George A (2004) The CCAAT enhancer-binding protein (C/EBP)beta and Nrf1 interact to regulate dentin sialophosphoprotein (DSPP) gene expression during odontoblast differentiation. J Biol Chem 279:45423–45432

    PubMed  CAS  Google Scholar 

  54. Xing W, Singgih A, Kapoor A, Alarcon CM, Baylink DJ, Mohan S (2007) Nuclear factor-E2-related factor-1 mediates ascorbic acid induction of osterix expression via interaction with antioxidant-responsive element in bone cells. J Biol Chem 282:22052–22061

    PubMed  CAS  Google Scholar 

  55. Biswas M, Chan JY (2010) Role of Nrf1 in antioxidant response element-mediated gene expression and beyond. Toxicol Appl Pharmacol 244:16–20

    PubMed  CAS  Google Scholar 

  56. Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, Lin W, Reddy B, Chan JY, Kong AN (2006) Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6 J mice and C57BL/6 J/Nrf2 (−/−) mice. Cancer Lett 243:170–192

    PubMed  CAS  Google Scholar 

  57. Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116

    PubMed  CAS  Google Scholar 

  58. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209

    PubMed  CAS  Google Scholar 

  59. Keum YS, Owuor ED, Kim BR, Hu R, Kong AN (2003) Involvement of Nrf2 and JNK1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent phenethyl isothiocyanate (PEITC). Pharm Res 20:1351–1356

    PubMed  CAS  Google Scholar 

  60. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86

    PubMed  CAS  Google Scholar 

  61. Zhang Y, Crouch DH, Yamamoto M, Hayes JD (2006) Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum. Biochem J 399:373–385

    PubMed  CAS  Google Scholar 

  62. Zhang Y, Lucocq JM, Hayes JD (2009) The Nrf1 CNC/bZIP protein is a nuclear envelope-bound transcription factor that is activated by t-butyl hydroquinone but not by endoplasmic reticulum stressors. Biochem J 418:293–310

    PubMed  CAS  Google Scholar 

  63. Zhang Y, Hayes JD (2010) Identification of topological determinants in the N-terminal domain of transcription factor Nrf1 that control its orientation in the endoplasmic reticulum membrane. Biochem J 430:497–510

    PubMed  CAS  Google Scholar 

  64. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196–5203

    PubMed  CAS  Google Scholar 

  65. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332

    PubMed  CAS  Google Scholar 

  66. Kelsen SG, Duan X, Ji R, Perez O, Liu C, Merali S (2008) Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. Am J Respir Cell Mol Biol 38:541–550

    PubMed  CAS  Google Scholar 

  67. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16:1345–1355

    PubMed  CAS  Google Scholar 

  68. Chen C, Yu R, Owuor ED, Kong AN (2000) Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch Pharm Res 23:605–612

    PubMed  CAS  Google Scholar 

  69. Cullinan SB, Diehl JA (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279:20108–20117

    PubMed  CAS  Google Scholar 

  70. He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J (2001) Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem 276:20858–20865

    PubMed  CAS  Google Scholar 

  71. Chapple SJ, Siow RC, Mann GE (2012) Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int J Biochem Cell Biol 44:1315–1320

    PubMed  CAS  Google Scholar 

  72. Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278(10):8135–8145

    PubMed  CAS  Google Scholar 

  73. Lee S, Hur EG, Ryoo IG, Jung KA, Kwak J, Kwak MK (2012) Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic β-cells. Toxicol Appl Pharmacol 264:431–438

    PubMed  CAS  Google Scholar 

  74. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW (2003) Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23:8786–8794

    PubMed  CAS  Google Scholar 

  75. Shinkai Y, Sumi D, Fukami I, Ishii T, Kumagai Y (2006) Sulforaphane, an activator of Nrf2, suppresses cellular accumulation of arsenic and its cytotoxicity in primary mouse hepatocytes. FEBS Lett 580:1771–1774

    PubMed  CAS  Google Scholar 

  76. Pickering AM, Linder RA, Zhang H, Forman HJ, Davies KJ (2012) Nrf2-dependent induction of proteasome and Pa28αβ regulator are required for adaptation to oxidative stress. J Biol Chem 287:10021–10031

    PubMed  CAS  Google Scholar 

  77. Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, Lin W, Reddy B, Chan JY, Kong AN (2006) Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray. Life Sci 79:1944–1955

    PubMed  CAS  Google Scholar 

  78. Niture SK, Jaiswal AK (2010) Hsp90 interaction with INrf2(Keap1) mediates stress-induced Nrf2 activation. J Biol Chem 285:36865–36875

    PubMed  CAS  Google Scholar 

  79. Yenki P, Khodagholi F, Shaerzadeh F (2013) Inhibition of phosphorylation of JNK suppresses Aβ-induced ER stress and upregulates prosurvival mitochondrial proteins in rat hippocampus. J Mol Neurosci 49:262–269

    PubMed  CAS  Google Scholar 

  80. Verma G, Datta M (2010) IL-1beta induces ER stress in a JNK dependent manner that determines cell death in human pancreatic epithelial MIA PaCa-2 cells. Apoptosis 15:864–876

    PubMed  CAS  Google Scholar 

  81. Riley BE, Kaiser SE, Kopito RR (2011) Autophagy inhibition engages Nrf2-p62 Ub-associated signaling. Autophagy 7:338–340

    PubMed  Google Scholar 

  82. Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T, Hipp MS, Lage K, Xavier RJ, Ryu KY, Taguchi K, Yamamoto M, Tanaka K, Mizushima N, Komatsu M, Kopito RR (2010) Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J Cell Biol 191(3):537–552

    PubMed  CAS  Google Scholar 

  83. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12:213–223

    PubMed  CAS  Google Scholar 

  84. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, Zhang DD (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30:3275–3285

    PubMed  CAS  Google Scholar 

  85. Rao VA, Klein SR, Bonar SJ, Zielonka J, Mizuno N, Dickey JS, Keller PW, Joseph J, Kalyanaraman B, Shacter E (2010) The antioxidant transcription factor Nrf2 negatively regulates autophagy and growth arrest induced by the anticancer redox agent mitoquinone. J Biol Chem 285:34447–34459

    PubMed  CAS  Google Scholar 

  86. Zhou Y, Wang HD, Zhu L, Cong ZX, Li N, Ji XJ, Pan H, Wang JW, Li WC (2013) Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line. Oncol Rep 29:394–400

    PubMed  CAS  Google Scholar 

  87. Zhao Z, Chen Y, Wang J, Sternberg P, Freeman ML, Grossniklaus HE, Cai J (2011) Age-related retinopathy in NRF2-deficient mice. PLoS ONE 6:e19456

    PubMed  CAS  Google Scholar 

  88. Stępkowski TM, Kruszewski MK (2011) Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. Free Radic Biol Med 50:1186–1195

    PubMed  Google Scholar 

  89. Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øvervatn A, McMahon M, Hayes JD, Johansen T (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285:22576–22591

    PubMed  CAS  Google Scholar 

  90. Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, Moscat J (2008) The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell 13:343–354

    PubMed  CAS  Google Scholar 

  91. Israël A (2010) The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol 2:a000158

    PubMed  Google Scholar 

  92. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW (2010) When NRF2 talks, who’s listening? Antioxid Redox Signal 13:1649–1663

    PubMed  CAS  Google Scholar 

  93. Copetti T, Bertoli C, Dalla E, Demarchi F, Schneider C (2009) p65/RelA modulates BECN1 transcription and autophagy. Mol Cell Biol 29:2594–2608

    PubMed  CAS  Google Scholar 

  94. Nivon M, Richet E, Codogno P, Arrigo AP, Kretz-Remy C (2009) Autophagy activation by NFkappaB is essential for cell survival after heat shock. Autophagy 5:766–783

    PubMed  CAS  Google Scholar 

  95. Djavaheri-Mergny M, Amelotti M, Mathieu J, Besançon F, Bauvy C, Souquère S, Pierron G, Codogno P (2006) NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. J Biol Chem 281:30373–30382

    PubMed  CAS  Google Scholar 

  96. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    PubMed  CAS  Google Scholar 

  97. Mattson MP, Meffert MK (2006) Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 13:852–860

    PubMed  CAS  Google Scholar 

  98. Comb WC, Cogswell P, Sitcheran R, Baldwin AS (2011) IKK-dependent, NF-κB-independent control of autophagic gene expression. Oncogene 30(14):1727–1732

    PubMed  CAS  Google Scholar 

  99. Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I, Kepp O, Tasdemir E, Galluzzi L, Shen S, Tailler M, Delahaye N, Tesniere A, De Stefano D, Younes AB, Harper F, Pierron G, Lavandero S, Zitvogel L, Israel A, Baud V, Kroemer G (2010) The IKK complex contributes to the induction of autophagy. EMBO J 29:619–631

    PubMed  CAS  Google Scholar 

  100. Dan HC, Baldwin AS (2008) Differential involvement of IkappaB kinases alpha and beta in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt. J Immunol 180:7582–7589

    PubMed  CAS  Google Scholar 

  101. Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei Y, Sun HL, Li LY, Ping B, Huang WC, He X, Hung JY, Lai CC, Ding Q, Su JL, Yang JY, Sahin AA, Hortobagyi GN, Tsai FJ, Tsai CH, Hung MC (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130:440–455

    PubMed  CAS  Google Scholar 

  102. Duran A, Amanchy R, Linares JF, Joshi J, Abu-Baker S, Porollo A, Hansen M, Moscat J, Diaz-Meco MT (2011) p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell 44(1):134–146

    PubMed  CAS  Google Scholar 

  103. Fan W, Tang Z, Chen D, Moughon D, Ding X, Chen S, Zhu M, Zhong Q (2010) Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy. Autophagy 6:614–621

    PubMed  CAS  Google Scholar 

  104. Zhang Y, Lucocq JM, Yamamoto M, Hayes JD (2007) The NHB1 (N-terminal homology box 1) sequence in transcription factor Nrf1 is required to anchor it to the endoplasmic reticulum and also to enable its asparagine-glycosylation. Biochem J 408:161–172

    PubMed  CAS  Google Scholar 

  105. Steffen J, Seeger M, Koch A, Krüger E (2010) Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell 40:147–158

    PubMed  CAS  Google Scholar 

  106. Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ (2010) Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell 38:17–28

    PubMed  CAS  Google Scholar 

  107. Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y (2009) ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci USA 106:2200–2205

    PubMed  CAS  Google Scholar 

  108. Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, Hahn S, Schreiber S, Wilhelm S, Herrmann M, Jäck HM, Voll RE (2007) Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 67:1783–1792

    PubMed  CAS  Google Scholar 

  109. Angeloni C, Motori E, Fabbri D, Malaguti M, Leoncini E, Lorenzini A, Hrelia S (2011) H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3 K/Akt activation. Am J Physiol Heart Circ Physiol 300:H2196–H2205

    PubMed  CAS  Google Scholar 

  110. Chepelev NL, Bennitz JD, Huang T, McBride S, Willmore WG (2011) The Nrf1 CNC-bZIP protein is regulated by the proteasome and activated by hypoxia. PLoS ONE 6:e29167

    PubMed  CAS  Google Scholar 

  111. Wang W, Chan JY (2006) Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function. J Biol Chem 281:19676–19687

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Authors acknowledge the funding support by Shahid Beheshti University of Medical Science to H.D. and F.K.H. and National Elite Fund, Iran, for the award of Young Scientist Research Fellowship to F.K.H. and funds by the University of Arkansas (Startup fund) and Center for Translational Neuroscience (UAMS-COBRE), to M.K.

Author information

Authors and Affiliations

  1. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hadi Digaleh & Fariba Khodagholi

  2. Department of Neurobiology and Developmental Sciences, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Mahmoud Kiaei

Authors
  1. Hadi Digaleh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud Kiaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fariba Khodagholi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fariba Khodagholi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Digaleh, H., Kiaei, M. & Khodagholi, F. Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy. Cell. Mol. Life Sci. 70, 4681–4694 (2013). https://doi.org/10.1007/s00018-013-1409-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1409-y

Keywords

Search

Navigation