Advertisement

Cellular and Molecular Life Sciences

, Volume 70, Issue 14, pp 2425–2441 | Cite as

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress

  • Shane Deegan
  • Svetlana Saveljeva
  • Adrienne M. Gorman
  • Afshin Samali
Review

Abstract

Macroautophagy (autophagy) is a cellular catabolic process which can be described as a self-cannibalism. It serves as an essential protective response during conditions of endoplasmic reticulum (ER) stress through the bulk removal and degradation of unfolded proteins and damaged organelles; in particular, mitochondria (mitophagy) and ER (reticulophagy). Autophagy is genetically regulated and the autophagic machinery facilitates removal of damaged cell components and proteins; however, if the cell stress is acute or irreversible, cell death ensues. Despite these advances in the field, very little is known about how autophagy is initiated and how the autophagy machinery is transcriptionally regulated in response to ER stress. Some three dozen autophagy genes have been shown to be required for the correct assembly and function of the autophagic machinery; however; very little is known about how these genes are regulated by cellular stress. Here, we will review current knowledge regarding how ER stress and the unfolded protein response (UPR) induce autophagy, including description of the different autophagy-related genes which are regulated by the UPR.

Keywords

Apoptosis ATG genes Autophagy Cell stress Chaperone Unfolded protein response 

Notes

Acknowledgments

Our research is supported by Science Foundation Ireland (09/RFP/BIC2371; 09/RFP/BMT2153), the Health Research Board (HRA/2009/59) and Breast Cancer Campaign (2008NovPhD21; 2010NovPR13).

References

  1. 1.
    McLaughlin M, Vandenbroeck K (2011) The endoplasmic reticulum protein folding factory and its chaperones: new targets for drug discovery? Br J Pharmacol 162:328–345. doi: 10.1111/j.1476-5381.2010.01064.x Google Scholar
  2. 2.
    Gotoh T, Endo M, Oike Y (2011) Endoplasmic reticulum stress-related inflammation and cardiovascular diseases. Int J Inflam 2011, Article ID 259462Google Scholar
  3. 3.
    Gorman AM, Healy SJ, Jager R, Samali A (2012) Stress management at the ER: regulators of ER stress-induced apoptosis. Pharmacol Ther. doi: 10.1016/j.pharmthera.2012.02.003
  4. 4.
    Cawley K, Deegan S, Samali A, Gupta S (2011) In: Michael Conn P (ed) Methods in enzymology, vol 490. Academic, London, p 31–51Google Scholar
  5. 5.
    Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885PubMedCrossRefGoogle Scholar
  6. 6.
    Reddy RK et al (2003) Endoplasmic Reticulum Chaperone protein GRP78 protects Cells from apoptosis induced by topoisomerase inhibitors. J Biol Chem 278:20915–20924. doi: 10.1074/jbc.M212328200 Google Scholar
  7. 7.
    Goldson TM et al (2007) Eukaryotic initiation factor 4E variants alter the morphology, proliferation, and colony-formation properties of MDA-MB-435 cancer cells. Mol Carcinog 46:71–84. doi: 10.1002/mc.20276 Google Scholar
  8. 8.
    Saito A et al (2011) Endoplasmic reticulum stress response mediated by the PERK-eIF2α-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem 286:4809–4818. doi: 10.1074/jbc.M110.152900 Google Scholar
  9. 9.
    Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904PubMedCrossRefGoogle Scholar
  10. 10.
    Harding HP et al (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633. doi: 10.1016/s1097-2765(03)00105-9 Google Scholar
  11. 11.
    Woo CW et al (2009) Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. Nat Cell Biol 11:1473–1480. doi:http://www.nature.com/ncb/journal/v11/n12/suppinfo/ncb1996_S1.html
  12. 12.
    McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21:1249–1259PubMedCrossRefGoogle Scholar
  13. 13.
    Cazanave SC et al (2010) CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 299:29CrossRefGoogle Scholar
  14. 14.
    Puthalakath H et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349PubMedCrossRefGoogle Scholar
  15. 15.
    Kim H et al (2009) Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 36:487–499PubMedCrossRefGoogle Scholar
  16. 16.
    Oyadomari S et al (2002) Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Investig 109:525–532PubMedGoogle Scholar
  17. 17.
    Chan JY, Kwong M (2000) Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Biochim Biophys Acta 15:19–26Google Scholar
  18. 18.
    Cullinan SB et al (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209. doi: 10.1128/mcb.23.20.7198-7209.2003 Google Scholar
  19. 19.
    Ho HK et al (2005) Nrf2 activation involves an oxidative-stress independent pathway in tetrafluoroethylcysteine-induced cytotoxicity. Toxicol Sci 86:354–364. doi: 10.1093/toxsci/kfi205 Google Scholar
  20. 20.
    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. doi: 10.1016/j.biocel.2005.09.018 Google Scholar
  21. 21.
    Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10:3787–3799PubMedGoogle Scholar
  22. 22.
    Shen J, Chen X, Hendershot L, Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3:99–111PubMedCrossRefGoogle Scholar
  23. 23.
    Ye J et al (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364. doi: 10.1016/s1097-2765(00)00133-7 Google Scholar
  24. 24.
    Li M et al (2000) ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1. Mol Cell Biol 20:5096–5106. doi: 10.1128/mcb.20.14.5096-5106.2000
  25. 25.
    Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K (2004) Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem 136:343–350PubMedCrossRefGoogle Scholar
  26. 26.
    Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K (2004) Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem 136:343–350. doi: 10.1093/jb/mvh122 Google Scholar
  27. 27.
    Belmont PJ, Chen WJ, Thuerauf DJ, Glembotski CC (2012) Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response. J Mol Cell Cardiol 52:1176–1182. doi: 10.1016/j.yjmcc.2012.01.017 Google Scholar
  28. 28.
    Kaufman RJ, Cao S (2010) Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism. EMBO Mol Med 2:189–192. doi: 10.1002/emmm.201000076
  29. 29.
    Hocking LJ, Mellis DJ, McCabe PS, Helfrich MH, Rogers MJ (2010) Functional interaction between sequestosome-1/p62 and autophagy-linked FYVE-containing protein WDFY3 in human osteoclasts. Biochem Biophys Res Commun 402:543–548. doi: 10.1016/j.bbrc.2010.10.076 Google Scholar
  30. 30.
    Korennykh AV et al (2009) The unfolded protein response signals through high-order assembly of Ire1. Nature 457:687–693. doi:http://www.nature.com/nature/journal/v457/n7230/suppinfo/nature07661_S1.html Google Scholar
  31. 31.
    Lin JH et al (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science 318:944–949. doi: 10.1126/science.1146361 Google Scholar
  32. 32.
    Trevino LR et al (2009) Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41:1001–1005. doi:http://www.nature.com/ng/journal/v41/n9/suppinfo/ng.432_S1.html Google Scholar
  33. 33.
    Drogat B et al (2007) IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res 67:6700-6707. doi: 10.1158/0008-5472.can-06-3235 Google Scholar
  34. 34.
    Wang FM, Chen YJ, Ouyang HJ (2010) Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation. Biochem J 433:245–252. doi: 10.1042/bj20101293 Google Scholar
  35. 35.
    Urano F et al (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666. doi: 10.1126/science.287.5453.664 Google Scholar
  36. 36.
    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 26:931–935PubMedCrossRefGoogle Scholar
  37. 37.
    Rouschop KM et al (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120:127–141. doi: 10.1172/JCI40027 Google Scholar
  38. 38.
    Jin HO et al (2009) Activating transcription factor 4 and CCAAT/enhancer-binding protein-beta negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress. Free Radic Biol Med 46:1158–1167. doi: 10.1016/j.freeradbiomed.2009.01.015
  39. 39.
    Doyle KM et al (2011) Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med 15:2025–2039. doi: 10.1111/j.1582-4934.2011.01374.x Google Scholar
  40. 40.
    Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885. doi: 10.1038/sj.embor.7400779 Google Scholar
  41. 41.
    Gupta S et al (2010) Mechanisms of ER stress-mediated mitochondrial membrane permeabilization. Int J Cell Biol 2010, Article ID 170215Google Scholar
  42. 42.
    De Duve C, Wattiaux R (1966) Functions of lysosomes. Annu Rev Physiol 28:435–492. doi: 10.1146/annurev.ph.28.030166.002251 Google Scholar
  43. 43.
    Ohsumi Y (1999) Molecular mechanism of autophagy in yeast, Saccharomyces cerevisiae. Philos Trans R Soc Lond B 354:1577–1580. doi: 10.1098/rstb.1999.0501(discussion 1580–1571)
  44. 44.
    Rubinsztein DC (2010) Autophagy: where next? EMBO Rep 11:3PubMedCrossRefGoogle Scholar
  45. 45.
    Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5:726–734. doi: 10.1038/nrc1692 Google Scholar
  46. 46.
    Moretti L, Cha YI, Niermann KJ, Lu B (2007) Switch between apoptosis and autophagy: radiation-induced endoplasmic reticulum stress? Cell Cycle 6:793–798 (pii: 4036)Google Scholar
  47. 47.
    Levine B (2007) Cell biology: autophagy and cancer. Nature 446:745–747. doi: 10.1038/446745a Google Scholar
  48. 48.
    Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293. doi: 10.1016/j.molcel.2010.09.023 Google Scholar
  49. 49.
    Rosenfeldt MT, Ryan KM (2009) The role of autophagy in tumour development and cancer therapy. Expert Rev Mol Med 11:e36Google Scholar
  50. 50.
    Weidberg H, Shvets E, Elazar Z (2011) Biogenesis and cargo selectivity of autophagosomes. Annu Rev Biochem 80:125–156. doi: 10.1146/annurev-biochem-052709-094552 Google Scholar
  51. 51.
    Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873. doi: 10.1101/gad.1599207 Google Scholar
  52. 52.
    Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741–752. doi: 10.1038/nrm2239 Google Scholar
  53. 53.
    Jung CH et al (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20:1992–2003. doi: 10.1091/mbc.E08-12-1249 Google Scholar
  54. 54.
    Egan DF et al (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461. doi: 10.1126/science.1196371 Google Scholar
  55. 55.
    Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141. doi: 10.1038/ncb2152 Google Scholar
  56. 56.
    Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9:563–575. doi:  10.1038/nrc2676 Google Scholar
  57. 57.
    Hosokawa N et al (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20:1981–1991. doi: 10.1091/mbc.E08-12-1248 Google Scholar
  58. 58.
    Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR (2011) ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7:737–747PubMedCrossRefGoogle Scholar
  59. 59.
    Loffler AS et al (2011) Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 7:696–706PubMedCrossRefGoogle Scholar
  60. 60.
    Chan EY (2012) Regulation and function of uncoordinated-51 like kinase proteins. Antioxid Redox Signal 17:775–785. doi: 10.1089/ars.2011.4396
  61. 61.
    Simonsen A, Tooze SA (2009) Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol 186:773–782. doi: 10.1083/jcb.200907014 Google Scholar
  62. 62.
    Polson HE et al (2010) Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6:506–522Google Scholar
  63. 63.
    Proikas-Cezanne T et al (2004) WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23:9314–9325. doi: 10.1038/sj.onc.1208331 Google Scholar
  64. 64.
    Axe EL et al (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701. doi: 10.1083/jcb.200803137 Google Scholar
  65. 65.
    Simonsen A et al (2004) Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J Cell Sci 117:4239–4251. doi: 10.1242/jcs.01287 Google Scholar
  66. 66.
    Stromhaug PE, Berg TO, Fengsrud M, Seglen PO (1998) Purification and characterization of autophagosomes from rat hepatocytes. Biochem J 335(Pt 2):217–224PubMedGoogle Scholar
  67. 67.
    Fengsrud M et al (1995) Ultrastructural and immunocytochemical characterization of autophagic vacuoles in isolated hepatocytes: effects of vinblastine and asparagine on vacuole distributions. Exp Cell Res 221:504–519. doi: 10.1006/excr.1995.1402
  68. 68.
    Hailey DW et al (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656–667. doi: 10.1016/j.cell.2010.04.009 Google Scholar
  69. 69.
    Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC (2010) Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 12:747–757. doi: 10.1038/ncb2078 Google Scholar
  70. 70.
    Rubinsztein DC, Shpilka T, Elazar Z (2012) Mechanisms of autophagosome biogenesis. Curr Biol 22:R29–R34. doi: 10.1016/j.cub.2011.11.034 Google Scholar
  71. 71.
    Mizushima N et al (2003) Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12–Apg5 conjugate. J Cell Sci 116:1679–1688PubMedCrossRefGoogle Scholar
  72. 72.
    Pankiv S et al (2010) FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J Cell Biol 188:253–269. doi: 10.1083/jcb.200907015 Google Scholar
  73. 73.
    Knaevelsrud H, Simonsen A (2010) Fighting disease by selective autophagy of aggregate-prone proteins. FEBS Lett 584:2635–2645. doi: 10.1016/j.febslet.2010.04.041 Google Scholar
  74. 74.
    Hirota Y, Aoki Y, Kanki T (2011) Mitophagy: selective degradation of mitochondria by autophagy. Seikagaku J Jpn Biochem Soc 83:126–130Google Scholar
  75. 75.
    Bernales S, Schuck S, Walter P (2007) ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3:285–287PubMedGoogle Scholar
  76. 76.
    Kraft C, Deplazes A, Sohrmann M, Peter M (2008) Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nature Cell Biol 10:602–610. doi: 10.1038/ncb1723 Google Scholar
  77. 77.
    Sakai Y, Oku M, van der Klei IJ, Kiel JA (2006) Pexophagy: autophagic degradation of peroxisomes. Biochim Biophys Acta 1763:1767–1775. doi: 10.1016/j.bbamcr.2006.08.023 Google Scholar
  78. 78.
    Glaumann H (1989) Crinophagy as a means for degrading excess secretory proteins in rat liver. Rev Biol Celular RBC 20:97–110Google Scholar
  79. 79.
    Mousavi SA et al (2001) Effects of inhibitors of the vacuolar proton pump on hepatic heterophagy and autophagy. Biochim Biophys Acta 1510:243–257PubMedCrossRefGoogle Scholar
  80. 80.
    Knodler LA, Celli J (2011) Eating the strangers within: host control of intracellular bacteria via xenophagy. Cell Microbiol 13:1319–1327. doi: 10.1111/j.1462-5822.2011.01632.x Google Scholar
  81. 81.
    Yamamoto A, Simonsen A (2011) The elimination of accumulated and aggregated proteins: a role for aggrephagy in neurodegeneration. Neurobiol Dis 43:17–28. doi: 10.1016/j.nbd.2010.08.015 Google Scholar
  82. 82.
    Weidberg H, Shvets E, Elazar Z (2009) Lipophagy: selective catabolism designed for lipids. Dev Cell 16:628–630. doi: 10.1016/j.devcel.2009.05.001 Google Scholar
  83. 83.
    Kristensen AR et al (2008) Ordered organelle degradation during starvation-induced autophagy. Mol Cell Proteomics MCP 7:2419–2428. doi: 10.1074/mcp.M800184-MCP200 Google Scholar
  84. 84.
    Sandilands E et al (2012) Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling. Nat Cell Biol 14:51–60. doi: 10.1038/ncb2386 Google Scholar
  85. 85.
    Wild P et al (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–233. doi: 10.1126/science.1205405 Google Scholar
  86. 86.
    Kirkin V, McEwan DG, Novak I, Dikic I (2009) A role for ubiquitin in selective autophagy. Mol Cell 34:259–269. doi: 10.1016/j.molcel.2009.04.026 Google Scholar
  87. 87.
    Ivanov S, Roy CR (2009) NDP52: the missing link between ubiquitinated bacteria and autophagy. Nat Immunol 10:1137–1139. doi: 10.1038/ni1109-1137 Google Scholar
  88. 88.
    Novak I et al (2010) Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 11:45–51. doi: 10.1038/embor.2009.256 Google Scholar
  89. 89.
    Tolkovsky AM (2009) Mitophagy. Biochim Biophys Acta 1793:1508–1515. doi: 10.1016/j.bbamcr.2009.03.002 Google Scholar
  90. 90.
    Narendra DP, Youle RJ (2011) Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid Redox Signal 14:1929–1938. doi: 10.1089/ars.2010.3799
  91. 91.
    Ding WX et al (2010) Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J Biol Chem 285:27879–27890. doi: 10.1074/jbc.M110.119537 Google Scholar
  92. 92.
    Gao W, Ding W-X, Stolz DB, Yin X-M (2008) Induction of macroautophagy by exogenously introduced calcium. Autophagy 4:754–761PubMedGoogle Scholar
  93. 93.
    Høyer-Hansen M et al (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-β, and Bcl-2. Mol Cell 25:193–205. doi: 10.1016/j.molcel.2006.12.009 Google Scholar
  94. 94.
    Egan DF et al (2010) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461. doi: 10.1126/science.1196371 Google Scholar
  95. 95.
    Ferrari D et al (2002) Endoplasmic reticulum, Bcl-2 and Ca2+ handling in apoptosis. Cell Calcium 32:413–420. doi: 10.1016/s0143416002002014 Google Scholar
  96. 96.
    Bassik MC, Scorrano L, Oakes SA, Pozzan T, Korsmeyer SJ (2004) Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. EMBO J 23:1207–1216. doi:http://www.nature.com/emboj/journal/v23/n5/suppinfo/7600104a_S1.html Google Scholar
  97. 97.
    Li G et al (2009) Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol 186:783–792. doi: 10.1083/jcb.200904060 Google Scholar
  98. 98.
    Ramming T, Appenzeller-Herzog C (2012) The physiological functions of mammalian endoplasmic oxidoreductin 1 (Ero1): on disulfides and more. Antioxid Redox Signal 16:1109–1118. doi: 10.1089/ars.2011.4475
  99. 99.
    Jia W, Pua HH, Li QJ, He YW (2011) Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes. J Immunol 186:1564–1574. doi: 10.4049/jimmunol.1001822 Google Scholar
  100. 100.
    Whitney ML, Jefferson LS, Kimball SR (2009) ATF4 is necessary and sufficient for ER stress-induced upregulation of REDD1 expression. Biochem Biophys Res Commun 379:451–455PubMedCrossRefGoogle Scholar
  101. 101.
    Jin HO et al (2009) Activating transcription factor 4 and CCAAT/enhancer-binding protein-β negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress. Free Radic Biol Med 46:1158–1167. doi: 10.1016/j.freeradbiomed.2009.01.015
  102. 102.
    Brugarolas J et al (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904. doi: 10.1101/gad.1256804 Google Scholar
  103. 103.
    Zhang H et al (2003) Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K–Akt signaling through downregulation of PDGFR. J Clin Invest 112:1223–1233PubMedGoogle Scholar
  104. 104.
    Gingras A-C, Kennedy SG, O’Leary MA, Sonenberg N, Hay N (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12:502–513PubMedCrossRefGoogle Scholar
  105. 105.
    Manning BD, Cantley LC (2003) United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 31:573–578PubMedCrossRefGoogle Scholar
  106. 106.
    Qin L, Wang Z, Tao L, Wang Y (2010) ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 6:239–247PubMedCrossRefGoogle Scholar
  107. 107.
    Salazar M et al (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Investig 119:1359–1372PubMedCrossRefGoogle Scholar
  108. 108.
    Yung HW, Charnock-Jones DS, Burton GJ (2011) Regulation of AKT phosphorylation at Ser473 and Thr308 by endoplasmic reticulum stress modulates substrate specificity in a severity dependent manner. PLoS One 6:e17894Google Scholar
  109. 109.
    Baumeister P et al (2005) Endoplasmic reticulum stress induction of the Grp78/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers. Mol Cell Biol 25:4529–4540. doi: 10.1128/mcb.25.11.4529-4540.2005
  110. 110.
    Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H (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. doi: 10.1038/sj.emboj.7600596 Google Scholar
  111. 111.
    Du K, Herzig S, Kulkarni RN, Montminy M (2003) TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300:1574–1577. doi: 10.1126/science.1079817 Google Scholar
  112. 112.
    Sinha S, Levine B (2000) The autophagy effector Beclin 1: a novel BH3-only protein. Oncogene 27:S137–S148Google Scholar
  113. 113.
    Boya P, Kroemer G (2009) Beclin 1: a BH3-only protein that fails to induce apoptosis. Oncogene 28:2125–2127PubMedCrossRefGoogle Scholar
  114. 114.
    McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21:1249–1259. doi: 10.1128/mcb.21.4.1249-1259.2001 Google Scholar
  115. 115.
    Szegezdi E, MacDonald DC, Ní Chonghaile T, Gupta S, Samali A (2009) Bcl-2 family on guard at the ER. Am J Physiol Cell Physiol 296:C941–C953. doi: 10.1152/ajpcell.00612.2008
  116. 116.
    Yamamoto K, Ichijo H, Korsmeyer SJ (1999) BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 19:8469–8478PubMedGoogle Scholar
  117. 117.
    Lei K, Davis RJ (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 100:2432–2437PubMedCrossRefGoogle Scholar
  118. 118.
    Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30:678–688. doi: 10.1016/j.molcel.2008.06.001 Google Scholar
  119. 119.
    Ogata M et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231. doi: 10.1128/MCB.01453-06 Google Scholar
  120. 120.
    Oh SH, Lim SC (2009) Endoplasmic reticulum stress-mediated autophagy/apoptosis induced by capsaicin (8-methyl-N-vanillyl-6-nonenamide) and dihydrocapsaicin is regulated by the extent of c-Jun NH2-terminal kinase/extracellular signal-regulated kinase activation in WI38 lung epithelial fibroblast cells. J Pharmacol Exp Ther 329:112–122. doi: 10.1124/jpet.108.144113
  121. 121.
    Gozuacik D et al (2008) DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ 15:1875–1886. doi: 10.1038/cdd.2008.121
  122. 122.
    Zalckvar E et al (2009) DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep 10:285–292. doi: 10.1038/embor.2008.246 Google Scholar
  123. 123.
    Kouroku Y et al (2007) ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 14:230–239. doi: 10.1038/sj.cdd.4401984 Google Scholar
  124. 124.
    Salih DAM, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136. doi: 10.1016/j.ceb.2008.02.005 Google Scholar
  125. 125.
    Medema RH, Jaattela M (2010) Cytosolic FoxO1: alive and killing. Nat Cell Biol 12:642–643PubMedCrossRefGoogle Scholar
  126. 126.
    Xu P, Das M, Reilly J, Davis RJ (2011) JNK regulates FoxO-dependent autophagy in neurons. Gene Dev 25:310–322. doi 10.1101/gad.1984311 Google Scholar
  127. 127.
    Zhao Y et al (2010) Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 12:665–675. doi:http://www.nature.com/ncb/journal/v12/n7/suppinfo/ncb2069_S1.html Google Scholar
  128. 128.
    Vidal RL et al (2012) Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Human Mol Genet 21:2245–2262. doi: 10.1093/hmg/dds040 Google Scholar
  129. 129.
    Malhotra D et al (2009) Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease: the role of Nrf2-regulated proteasomal activity. Am J Respir Crit Care Med 180:1196–1207. doi: 10.1164/rccm.200903-0324OC
  130. 130.
    Poon AH et al (2012) Genetic and histologic evidence for autophagy in asthma pathogenesis. J Allergy Clin Immunol 129:569–571. doi: 10.1016/j.jaci.2011.09.035 Google Scholar
  131. 131.
    Chen ZH et al (2008) Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PloS One 3:e3316. doi: 10.1371/journal.pone.0003316
  132. 132.
    Martinet W, Knaapen MW, Kockx MM, De Meyer GR (2007) Autophagy in cardiovascular disease. Trends Mol Med 13:482–491. doi: 10.1016/j.molmed.2007.08.004 Google Scholar
  133. 133.
    Minamino T, Kitakaze M (2010) ER stress in cardiovascular disease. J Mol Cell Cardiol 48:1105–1110. doi: 10.1016/j.yjmcc.2009.10.026 Google Scholar
  134. 134.
    Levine, B. & Kroemer, G. Autophagy in the Pathogenesis of Disease. Cell 132:27–42, doi: 10.1016/j.cell.2007.12.018 (2008)Google Scholar
  135. 135.
    Harding HP, Ron D (2002) Endoplasmic reticulum stress and the development of diabetes. Diabetes 51:S455–S461. doi: 10.2337/diabetes.51.2007.S455 Google Scholar
  136. 136.
    Herbert TP (2007) PERK in the life and death of the pancreatic β-cell. Biochem Soc Trans 35:1205–1207PubMedCrossRefGoogle Scholar
  137. 137.
    Liu Y et al Impaired autophagic function in rat islets with aging. Age 1–14. doi: 10.1007/s11357-012-9456-0
  138. 138.
    Quan W et al (2012) Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice. Diabetologia 55:392–403. doi: 10.1007/s00125-011-2350-y Google Scholar
  139. 139.
    Quan W, Lim Y-M, Lee M-S (2012) Role of autophagy in diabetes and endoplasmic reticulum stress of pancreatic β-cells. Exp Mol Med 44:81–88PubMedCrossRefGoogle Scholar
  140. 140.
    Martino L et al (2012) Palmitate activates autophagy in INS-1E β-cells and in isolated rat and human pancreatic islets. PLoS One 7:e36188. doi: 10.1371/journal.pone.0036188
  141. 141.
    Yin JJ, Li YB, Wang Y, Liu GD, Wang J, Zhu XO, Pan SH (2012) The role of autophagy in endoplasmic reticulum stress-induced pancreatic β cell death. Autophagy 8:158–164Google Scholar
  142. 142.
    Spencer B et al (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci Off J Soc Neurosci 29: 13578–13588. doi: 10.1523/JNEUROSCI.4390-09.2009 Google Scholar
  143. 143.
    Madeo F, Eisenberg T, Kroemer G (2009) Autophagy for the avoidance of neurodegeneration. Genes Dev 23:2253–2259. doi: 10.1101/gad.1858009 Google Scholar
  144. 144.
    Crews L et al (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PloS One 5:e9313. doi: 10.1371/journal.pone.0009313
  145. 145.
    Pickford F et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Investig 118:2190–2199. doi: 10.1172/JCI33585 Google Scholar
  146. 146.
    Michiorri S et al (2010) The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ 17:962–974. doi: 10.1038/cdd.2009.200 Google Scholar
  147. 147.
    Gorman AM (2008) Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med 12:2263–2280. doi: 10.1111/j.1582-4934.2008.00402.x Google Scholar
  148. 148.
    Garcia-Arencibia M, Hochfeld WE, Toh PP, Rubinsztein DC (2010) Autophagy, a guardian against neurodegeneration. Semin Cell Dev Biol 21:691–698. doi: 10.1016/j.semcdb.2010.02.008 Google Scholar
  149. 149.
    Valente EM et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160. doi: 10.1126/science.1096284 Google Scholar
  150. 150.
    Rami A (2009) Review: autophagy in neurodegeneration: firefighter and/or incendiarist? Neuropathol Appl Neurobiol 35:449–461. doi: 10.1111/j.1365-2990.2009.01034.x Google Scholar
  151. 151.
    Menzies FM, Rubinsztein DC (2010) Broadening the therapeutic scope for rapamycin treatment. Autophagy 6:286–287PubMedCrossRefGoogle Scholar
  152. 152.
    Hetz C et al (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294–2306. doi: 10.1101/gad.1830709 Google Scholar
  153. 153.
    Rao R. et al (2012) Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells. Mol Cancer Ther 11:973–983. doi: 10.1158/1535-7163.mct-11-0979
  154. 154.
    Thomas S et al Preferential killing of triple-negative breast cancer cells in vitro and in vivo when pharmacological aggravators of endoplasmic reticulum stress are combined with autophagy inhibitors. Cancer Lett 325:63–71. doi: 10.1016/j.canlet.2012.05.030
  155. 155.
    Jia L, Gopinathan G, Sukumar JT, Gribben JG (2012) Blocking autophagy prevents bortezomib-induced NF-κB activation by reducing I-κBα degradation in lymphoma cells. PLoS One 7:e32584. doi: 10.1371/journal.pone.0032584
  156. 156.
    Debnath J (2011) The multifaceted roles of autophagy in tumors—implications for breast cancer. J Mammary Gland Biol Neoplasia 16:173–187. doi: 10.1007/s10911-011-9223-3 Google Scholar
  157. 157.
    Lozy F, Karantza V (2012) Autophagy and cancer cell metabolism. Semin Cell Dev Biol 23:395–401. doi: 10.1016/j.semcdb.2012.01.005 Google Scholar
  158. 158.
    Kang JH, Chang YC, Maurizi MR (2012) 4-O-carboxymethyl ascochlorin causes ER stress and induced autophagy in human hepatocellular carcinoma cells. J Biol Chem 287:15661–15671. doi: 10.1074/jbc.M112.358473 Google Scholar
  159. 159.
    Emdad L et al (2011) Is there a common upstream link for autophagic and apoptotic cell death in human high-grade gliomas? Neuro Oncol 13:725–735. doi: 10.1093/neuonc/nor053 Google Scholar

Copyright information

© Springer Basel 2012

Authors and Affiliations

  • Shane Deegan
    • 1
    • 2
  • Svetlana Saveljeva
    • 1
    • 2
  • Adrienne M. Gorman
    • 1
    • 2
  • Afshin Samali
    • 1
    • 2
  1. 1.Apoptosis Research CentreNUI GalwayGalwayIreland
  2. 2.School of Natural SciencesNUI GalwayGalwayIreland

Personalised recommendations