Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

Abstract

The endoplasmic reticulum ( ER ) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one‐third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response ( UPR ), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling‐centric view of ER functions, from the ER 's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR , its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 377

1. 1.

   Porter KR, Claude A & Fullam EF (1945 ) A study of tissue culture cells by electron microscopy: methods and preliminary observations. J Exp Med 81, 233–246.

   Not in our library10.1084/jem.81.3.233

2. 2.

   Palade GE & Porter KR (1954 ) Studies on the endoplasmic reticulum. I. Its identification in cells in situ. J Exp Med 100, 641–656.

   Not in our library10.1084/jem.100.6.641

3. 3.

   Alberts B, Johnson A, Lewis J, Raff M, Roberts K & Walter P (2002 ) Molecular Biology of the Cell, 4th edn. Garland Science, New York, NY.

   Not in our library

4. 4.

   Borgese N, Francolini M & Snapp E (2006 ) Endoplasmic reticulum architecture: structures in flux. Curr Opin Cell Biol 18, 358–364.

   Not in our library10.1016/j.ceb.2006.06.008

5. 5.

   Shibata Y, Voeltz GK & Rapoport TA (2006 ) Rough sheets and smooth tubules. Cell 126, 435–439.

   Not in our library10.1016/j.cell.2006.07.019

6. 6.

   Hayashi T, Rizzuto R, Hajnoczky G & Su TP (2009 ) MAM: more than just a housekeeper. Trends Cell Biol 19, 81–88.

   Not in our library10.1016/j.tcb.2008.12.002

7. 7.

   Toulmay A & Prinz WA (2011 ) Lipid transfer and signaling at organelle contact sites: the tip of the iceberg. Curr Opin Cell Biol 23, 458–463.

   Not in our library10.1016/j.ceb.2011.04.006

8. 8.

   Daste F, Galli T & Tareste D (2015 ) Structure and function of longin SNAREs. J Cell Sci 128, 4263–4272.

   Not in our library10.1242/jcs.178574

9. 9.

   Rowland AA, Chitwood PJ, Phillips MJ & Voeltz GK (2014 ) ER contact sites define the position and timing of endosome fission. Cell 159, 1027–1041.

   Not in our library10.1016/j.cell.2014.10.023

10. 10.

    Wilhelm LP, Tomasetto C & Alpy F (2016 ) Touché! STARD3 and STARD3NL tether the ER to endosomes. Biochem Soc Trans 44, 493–498.

    Not in our library10.1042/bst20150269

11. 11.

    Wilhelm LP, Wendling C, Védie B, Kobayashi T, Chenard M, Tomasetto C, Drin G & Alpy F (2017 ) STARD3 mediates endoplasmic reticulum‐to‐endosome cholesterol transport at membrane contact sites. EMBO J 36, 1412–1433.

    Not in our library10.15252/embj.201695917

12. 12.

    Henne WM, Zhu L, Balogi Z, Stefan C, Pleiss JA & Emr SD (2015 ) Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein. J Cell Biol 210, 541–551.

    Not in our library10.1083/jcb.201503088

13. 13.

    Hayashi‐Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T & Yamamoto A (2010 ) Electron tomography reveals the endoplasmic reticulum as a membrane source for autophagosome formation. Autophagy 6, 301–303.

    Not in our library10.4161/auto.6.2.11134

14. 14.

    Uemura T, Yamamoto M, Kametaka A, Sou Y, Yabashi A, Yamada A, Annoh H, Kametaka S, Komatsu M & Waguri S (2014 ) A cluster of thin tubular structures mediates transformation of the endoplasmic reticulum to autophagic isolation membrane. Mol Cell Biol 34, 1695–1706.

    Not in our library10.1128/mcb.01327-13

15. 15.

    Stefan CJ, Manford AG, Baird D, Yamada‐Hanff J, Mao Y & Emr SD (2011 ) Osh proteins regulate phosphoinositide metabolism at ER‐plasma membrane contact sites. Cell 144, 389–401.

    Not in our library10.1016/j.cell.2010.12.034

16. 16.

    Braakman I & Bulleid NJ (2011 ) Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem 80, 71–99.

    Not in our library10.1146/annurev-biochem-062209-093836

17. 17.

    Hebert DN & Molinari M (2007 ) In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol Rev 87, 1377–1408.

    Not in our library10.1152/physrev.00050.2006

18. 18.

    Wallis AK & Freedman RB (2013 ) Assisting oxidative protein folding: how do protein disulphide‐isomerases couple conformational and chemical processes in protein folding? Top Curr Chem 328, 1–34.

    Not in our library10.1007/128_2011_171

19. 19.

    Aebi M, Bernasconi R, Clerc S & Molinari M (2010 ) N‐glycan structures: recognition and processing in the ER. Trends Biochem Sci 35, 74–82.

    Not in our library10.1016/j.tibs.2009.10.001

20. 20.

    Meusser B, Hirsch C, Jarosch E & Sommer T (2005 ) ERAD: the long road to destruction. Nat Cell Biol 7, 766–772.

    Not in our library10.1038/ncb0805-766

21. 21.

    Hebert DN, Bernasconi R & Molinari M (2010 ) ERAD substrates: which way out? Semin Cell Dev Biol 21, 526–532.

    Not in our library10.1016/j.semcdb.2009.12.007

22. 22.

    Kobayashi T, Tanaka K, Inoue K & Kakizuka A (2002 ) Functional ATPase activity of p97/valosin‐containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells. J Biol Chem 277, 47358–47365.

    Not in our library10.1074/jbc.m207783200

23. 23.

    Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, Crimian R, Schoch K, Platt J, Cox R et al (2014 ) Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum‐associated degradation (ERAD) pathway. Genet Med 16, 751–758.

    Not in our library10.1038/gim.2014.22

24. 24.

    Kamhi‐Nesher S, Shenkman M, Tolchinsky S, Fromm SV, Ehrlich R & Lederkremer GZ (2001 ) A novel quality control compartment derived from the endoplasmic reticulum. Mol Biol Cell 12, 1711–1723.

    Not in our library10.1091/mbc.12.6.1711

25. 25.

    Huyer G, Longsworth GL, Mason DL, Mallampalli MP, McCaffery JM, Wright RL & Michaelis S (2004 ) A striking quality control subcompartment in Saccharomyces cerevisiae: the endoplasmic reticulum‐associated compartment. Mol Biol Cell 15, 908–921.

    Not in our library10.1091/mbc.e03-07-0546

26. 26.

    Brown MS & Goldstein JL (1999 ) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96, 11041–11048.

    Not in our library10.1073/pnas.96.20.11041

27. 27.
    Membrane phospholipid synthesis and endoplasmic reticulum function · 2009

    Not checked
28. 28.

    Yen C‐LE, Stone SJ, Koliwad S, Harris C & Farese RV (2008 ) Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 49, 2283–2301.

    Not in our library10.1194/jlr.r800018-jlr200

29. 29.

    Jo Y & DeBose‐Boyd RA (2010 ) Control of cholesterol synthesis through regulated ER‐associated degradation of HMG CoA reductase. Crit Rev Biochem Mol Biol 45, 185–198.

    Not in our library10.3109/10409238.2010.485605

30. 30.

    Patwardhan GA, Beverly LJ & Siskind LJ (2016 ) Sphingolipids and mitochondrial apoptosis. J Bioenerg Biomembr 48, 153–168.

    Not in our library10.1007/s10863-015-9602-3

31. 31.

    Barlowe C, Orci L, Yeung T, Hosobuchi M, Hamamoto S, Salama N, Rexach MF, Ravazzola M, Amherdt M & Schekman R (1994 ) COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum. Cell 77, 895–907.

    Not in our library10.1016/0092-8674(94)90138-4

32. 32.

    Siddiqi S, Saleem U, Abumrad NA, Davidson NO, Storch J, Siddiqi SA & Mansbach CM (2010 ) A novel multiprotein complex is required to generate the prechylomicron transport vesicle from intestinal ER. J Lipid Res 51, 1918–1928.

    Not in our library10.1194/jlr.m005611

33. 33.

    Clapham DE (2007 ) Calcium signaling. Cell 131, 1047–1058.

    Not in our library10.1016/j.cell.2007.11.028

34. 34.

    Meldolesi J & Pozzan T (1998 ) The endoplasmic reticulum Ca2 + store: a view from the lumen. Trends Biochem Sci 23, 10–14.

    Not in our library10.1016/s0968-0004(97)01143-2

35. 35.

    Hetz C (2012 ) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13, 89–102.

    Not in our library10.1038/nrm3270

36. 36.

    Hanahan D & Weinberg RA (2011 ) Hallmarks of cancer: the next generation. Cell 144, 646–674.

    Not in our library10.1016/j.cell.2011.02.013

37. 37.

    Holderfield M, Deuker MM, McCormick F & McMahon M (2014 ) Targeting RAF kinases for cancer therapy: BRAF mutated melanoma and beyond. Nat Rev Cancer 14, 455–467.

    Not in our library10.1038/nrc3760

38. 38.

    Piwocka K, Vejda S, Cotter TG, O'Sullivan GC & McKenna SL (2006 ) Bcr‐Abl reduces endoplasmic reticulum releasable calcium levels by a Bcl‐2‐independent mechanism and inhibits calcium‐dependent apoptotic signaling. Blood 107, 4003–4010.

    Not in our library10.1182/blood-2005-04-1523

39. 39.

    Pluquet O, Pourtier A & Abbadie C (2015 ) The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. Am J Physiol Cell Physiol 308, C415–C425.

    Not in our library10.1152/ajpcell.00334.2014

40. 40.

    Chen H‐J, Anagnostou G, Chai A, Withers J, Morris A, Adhikaree J, Pennetta G & de Belleroche JS (2010 ) Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J Biol Chem 285, 40266–40281.

    Not in our library10.1074/jbc.m110.161398

Cited by papers we hold 15

• Microplastics and Oxidative Stress—Current Problems and Prospects · 2024
  No notice
• Updated mechanisms of MASLD pathogenesis · 2024
  No notice
• Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways · 2023
  No notice
• PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway · 2022
  Not checked
• ERN1 knockdown modifies the impact of glucose and glutamine deprivations on the expression of EDN1 and its receptors in glioma cells · 2021
  Not checked
• The Identification of a Novel Calcium-Dependent Link Between NAD+ and Glucose Deprivation-Induced Increases in Protein O-GlcNAcylation and ER Stress · 2021
  Not checked
• Regulation of lipid metabolism by the unfolded protein response · 2021
  No notice
• Roles of XBP1s in Transcriptional Regulation of Target Genes · 2021
  No notice
• Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy · 2021
  No notice
• ER Stress Responses: An Emerging Modulator for Innate Immunity · 2020
  No notice
• Excitotoxicity: Still Hammering the Ischemic Brain in 2020 · 2020
  No notice
• Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance · 2019
  No notice
• The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections · 2019
  No notice
• Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1 · 2019
  No notice
• Immunogenic Cell Death and Immunotherapy of Multiple Myeloma · 2019
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.