From recordings of disulfide isomerases in action
to reversal of maladaptive endoplasmic reticulum
stress responses: proceedings on the ER & Redox
Club Meeting held in Venice, April 2015

• Authors: Eelco van Anken
• Languages of publication: EN

Abstracts

EN

The endoplasmic reticulum (ER) interacts and
cooperates with other organelles as a central hub in cellular
homeostasis. In particular, the ER is the first station along the
secretory pathway, where client proteins fold and assemble
before they travel to their final destination elsewhere in the
endomembrane system or outside the cell. Protein folding
and disulfide bond formation go hand in hand in the ER, a
task that is achieved with the help of ER-resident chaperones
and other folding factors, including oxidoreductases that
catalyze disulfide bond formation. Yet, when their combined
effort is in vain, client proteins that fail to fold are disposed of
through ER-associated degradation (ERAD). The ER folding
and ERAD machineries can be boosted through the unfolded
protein response (UPR) if required. Still, protein folding in
the ER may consistently fail when proteins are mutated due
to a genetic defect, which, ultimately, can lead to disease.
Novel developments in all these fields of study and how
new insights ultimately can be exploited for clinical or
biotechnological purposes were highlighted in a rich variety
of presentations at the ER & Redox Club Meeting that was
held in Venice from 15 to 17 April 2015. As such, the meeting
provided the participants an excellent opportunity to mingle
and discuss key advancements and outstanding questions
on ER function in health and disease.

Keywords

EN

autophagy; BiP; chaperone; endoplasmicreticulum; ER-associated degradation; ER-stress; mitochondria; protein disulfide isomerase; proteinfolding; redox regulation; unfolded protein response

• Publisher: De Gruyter Open
• Journal: Endoplasmic Reticulum Stress in Diseases
• Year: 2015
• Volume: 2
• Issue: 1

Dates

online

21 - 8 - 2015

received

26 - 7 - 2015

accepted

26 - 7 - 2015

Contributors

author

Eelco van Anken

• San Raffaele Scientific
  Institute, Division of Genetics and Cell Biology & Università Vita-Salute,
  Milan, Italy

References

• [1] Balch WE et al. Adapting proteostasis for disease intervention.Science. 2008; 319(5865):916-9. [PubMed: 18276881]
• [2] Hartl FU Bracher A Hayer-Hartl M. Molecular chaperonesin protein folding and proteostasis. Nature. 2011;475(7356):324-32. [PubMed: 21776078]
• [3] Worby CA Dixon JE. Unpacking the unfolded protein response.Cell. 2014; 158(6):1221-4. [PubMed: 25215479]
• [4] Benham AM. Protein folding and disulfide bond formation inthe eukaryotic cell: meeting report based on the presentationsat the European Network Meeting on Protein Folding andDisulfide Bond Formation 2009 (Elsinore, Denmark). FEBS J.2009; 276(23):6905-11. [PubMed: 19860835]
• [5] Elbaz Y Schuldiner M. Staying in touch: the molecularera of organelle contact sites. Trends Biochem Sci. 2011;36(11):616-23. [PubMed: 21958688]
• [6] Naón D Scorrano L. At the right distance: ER-mitochondriajuxtaposition in cell life and death. Biochim Biophys Acta.2014; 1843(10):2184-94. [PubMed: 24875902]
• [7] de Brito OM Scorrano L. Mitofusin 2 tethers endoplasmicreticulum to mitochondria. Nature. 2008; 456(7222):605-10. [PubMed: 19052620]
• [8] Ast T Schuldiner M. All roads lead to Rome (but some maybe harder to travel): SRP-independent translocation into theendoplasmic reticulum. Crit Rev Biochem Mol Biol. 2013;48(3):273-88. [PubMed: 23530742]
• [9] Aviram N Schuldiner M. Embracing the void--how much dowe really know about targeting and translocation to theendoplasmic reticulum? Curr Opin Cell Biol. 2014; 29(8-17. [PubMed: 24662022]
• [10] Schäuble N et al. BiP-mediated closing of the Sec61 channellimits Ca2+ leakage from the ER. EMBO J. 2012; 31(15):3282-96. [PubMed: 22796945]
• [11] Geva Y Schuldiner M. The back and forth of cargo exit from theendoplasmic reticulum. Curr Biol 2014; 24(3):R130-6. [PubMed:24502791]
• [12] Fossati M Colombo SF Borgese N. A positive signal preventssecretory membrane cargo from recycling between theGolgi and the ER. EMBO J. 2014; 33(18):2080-97. [PubMed:25063674]
• [13] Spooner RA Lord JM. How ricin and Shiga toxin reach thecytosol of target cells: retrotranslocation from the endoplasmicreticulum. Curr Top Microbiol Immunol. 2012; 357(19-40. [PubMed: 21761287]
• [14] Stechmann B et al. Inhibition of retrograde transport protectsmice from lethal ricin challenge. Cell. 2010; 141(2):231-42. [PubMed: 20403321]
• [15] Ellgaard L Helenius A. Quality control in the endoplasmicreticulum. Nat Rev Mol Cell Biol. 2003; 4(3):181-91. [PubMed:12612637]
• [16] Behnke J Feige MJ Hendershot LM. BiP and its nucleotideexchange factors Grp170 and Sil1: mechanisms of actionand biological functions. J Mol Biol. 2015; 427(7):1589-608. [PubMed: 25698114]
• [17] Otero JH et al. Dissection of structural and functionalrequirements that underlie the interaction of ERdj3 protein withsubstrates in the endoplasmic reticulum. J Biol Chem. 2014;289(40):27504-12. [PubMed: 25143379]
• [18] Anelli T van Anken E. Missing links in antibody assemblycontrol. Int J Cell Biol. 2013; 606703. [PubMed: 24489546]
• [19] Shimizu Y Meunier L Hendershot LM. pERp1 is significantlyup-regulated during plasma cell differentiation and contributesto the oxidative folding of immunoglobulin. Proc Natl Acad SciU S A. 2009; 106(40):17013-8. [PubMed: 19805157]
• [20] van Anken E et al. Efficient IgM assembly and secretion requirethe plasma cell induced endoplasmic reticulum protein pERp1 Proc Natl Acad Sci U S A. 2009; 106(40):17019-24. [PubMed:19805154]
• [21] Bulleid NJ. Disulfide bond formation in the mammalianendoplasmic reticulum. Cold Spring Harb Perspect Biol. 2012;4(11):[PubMed: 23125019]
• [22] Bulleid NJ Ellgaard L. Multiple ways to make disulfides. TrendsBiochem Sci. 2011; 36(9):485-92. [PubMed: 21778060]
• [23] Tu BP Weissman JS. Oxidative protein folding in eukaryotes:mechanisms and consequences. J Cell Biol. 2004; 164(3):341-6. [PubMed: 14757749]
• [24] Wang L et al. Glutathione peroxidase 7 utilizes hydrogenperoxide generated by Ero1alpha to promote oxidative proteinfolding. Antioxid Redox Signal. 2014; 20(4):545-56. [PubMed:23919619]
• [25] Araki K Inaba K. Structure, mechanism, and evolution of Ero1family enzymes. Antioxid Redox Signal. 2012; 16(8):790-9. [PubMed: 22145624]
• [26] Battle DM et al. Expression of the endoplasmic reticulumoxidoreductase Ero1alpha in gastro-intestinal cancer revealsa link between homocysteine and oxidative protein folding.Antioxid Redox Signal. 2013; 19(1):24-35. [PubMed: 23373818]
• [27] Benham AM et al. Ero1-PDI interactions, the response to redoxflux and the implications for disulfide bond formation in themammalian endoplasmic reticulum. Philos Trans R Soc Lond BBiol Sci. 2013; 368(1617):20110403. [PubMed: 23530257]
• [28] Zhang L et al. Different interaction modes for protein-disulfideisomerase (PDI) as an efficient regulator and a specificsubstrate of endoplasmic reticulum oxidoreductin-1alpha(Ero1alpha). J Biol Chem. 2014; 289(45):31188-99. [PubMed:25258311]
• [29] Goldenberger RF Epstein CJ Anfinsen CB. Acceleration ofreactivation of reduced bovine panreatic ribonucleaseby a microsomal system from rat liver. J Biol Chem. 1963;238(2):628-35. [PubMed: 13948694]
• [30] Okumura M Kadokura H Inaba K. Structures and functionsof protein disulfide isomerase family members involved inproteostasis in the endoplasmic reticulum. Free Radic BiolMed. 2015; 83: 314-22. [PubMed: 25697777]
• [31] Ellgaard L Ruddock LW. The human protein disulphideisomerase family: substrate interactions and functionalproperties. EMBO Rep. 2005; 6(1):28-32. [PubMed: 15643448]
• [32] Anelli T et al. Thiol-mediated protein retention in theendoplasmic reticulum: the role of ERp44. EMBO J. 2003;22(19):5015-22. [PubMed: 14517240]
• [33] Kakihana T et al. Dynamic regulation of Ero1alpha and peroxiredoxin4 localization in the secretory pathway. J Biol Chem.2013; 288(41):29586-94. [PubMed: 23979138]
• [34] Fraldi A et al. Multistep, sequential control of the traffickingand function of the multiple sulfatase deficiency gene product,SUMF1 by PDI, ERGIC-53 and ERp44. Hum Mol Genet. 2008;17(17):2610-21. [PubMed: 18508857]
• [35] Anelli T et al. Ero1alpha regulates Ca(2+) fluxes at theendoplasmic reticulum-mitochondria interface (MAM). AntioxidRedox Signal. 2012; 16(10):1077-87. [PubMed: 21854214]
• [36] Vavassori S et al. A pH-regulated quality control cycle forsurveillance of secretory protein assembly. Mol Cell. 2013;50(6):783-92. [PubMed: 23685074]
• [37] Hagiwara M et al. Structural basis of an ERAD pathwaymediated by the ER-resident protein disulfide reductase ERdj5.Mol Cell. 2011; 41(4):432-44. [PubMed: 21329881]
• [38] Ushioda R et al. ERdj5 is required as a disulfide reductase fordegradation of misfolded proteins in the ER. Science. 2008;321(5888):569-72. [PubMed: 18653895]
• [39] Cormier JH et al. EDEM1 recognition and delivery of misfoldedproteins to the SEL1L-containing ERAD complex. Mol Cell. 2009;34(5):627-33. [PubMed: 19524542]
• [40] Marin MB et al. Tyrosinase degradation is prevented whenEDEM1 lacks the intrinsically disordered region. PloS one.2012; 7(8):e42998. [PubMed: 22905195]
• [41] Clerc S et al. Htm1 protein generates the N-glycan signal forglycoprotein degradation in the endoplasmic reticulum. J CellBiol. 2009; 184(1):159-72. [PubMed: 19124653]
• [42] Christianson JC Ye Y. Cleaning up in the endoplasmic reticulum:ubiquitin in charge. Nat Struct Mol Biol. 2014; 21(4):325-35. [PubMed: 24699081]
• [43] Kikkert M et al. Human HRD1 is an E3 ubiquitin ligase involvedin degradation of proteins from the endoplasmic reticulum. JBiol Chem. 2004; 279(5):3525-34. [PubMed: 14593114]
• [44] Wunderley L et al. SGTA regulates the cytosolic quality controlof hydrophobic substrates. J Cell Sci. 2014; 127(21):4728-39. [PubMed: 25179605]
• [45] Leznicki P High S. SGTA antagonizes BAG6-mediated proteintriage. Proc Natl Acad Sci U S A. 2012; 109(47):19214-9. [PubMed: 23129660]
• [46] Olzmann JA Kopito RR Christianson JC. The mammalianendoplasmic reticulum-associated degradation system. ColdSpring Harb Perspect Biol. 2013; 5(9):[PubMed: 23232094]
• [47] Fleig L et al. Ubiquitin-dependent intramembrane rhomboidprotease promotes ERAD of membrane proteins. Mol Cell. 2012;47(4):558-69. [PubMed: 22795130]
• [48] Walter P Ron D. The unfolded protein response: fromstress pathway to homeostatic regulation. Science. 2011;334(6059):1081-6. [PubMed: 22116877]
• [49] van Anken E et al. Sequential waves of functionally relatedproteins are expressed when B cells prepare for antibodysecretion. Immunity. 2003; 18(2):243-53. [PubMed:[Crossref]
• [50] Harding HP Zhang Y Ron D. Protein translation and folding arecoupled by an endoplasmic-reticulum-resident kinase. Nature.1999; 397(6716):271-4. [PubMed:
• [51] Sidrauski C et al. Pharmacological brake-release of mRNAtranslation enhances cognitive memory. eLife. 2013; 2:e00498. [PubMed: 23741617]
• [52] Sekine Y et al. Stress responses. Mutations in a translationinitiation factor identify the target of a memory-enhancingcompound. Science. 2015; 348(6238):1027-30. [PubMed:25858979]
• [53] Ma Y Hendershot LM. Delineation of a negative feedbackregulatory loop that controls protein translation duringendoplasmic reticulum stress. J Biol Chem. 2003;278(37):34864-73. [PubMed: 12840028]
• [54] Brush MH Weiser DC Shenolikar S. Growth arrest and DNAdamage-inducible protein GADD34 targets protein phosphatase1 alpha to the endoplasmic reticulum and promotes dephosphorylationof the alpha subunit of eukaryotic translationinitiation factor 2. Mol Cell Biol. 2003; 23(4):1292-303. [PubMed: 12556489]
• [55] Chen R et al. G-actin provides substrate-specificity toeukaryotic initiation factor 2alpha holophosphatases. eLife.2015; 4:04871 [PubMed: 25774600]
• [56] Li H et al. Mammalian endoplasmic reticulum stress sensorIRE1 signals by dynamic clustering. Proc Natl Acad Sci U S A.2010; 107(37):16113-8. [PubMed: 20798350]
• [57] Aragón T et al. Messenger RNA targeting to endoplasmicreticulum stress signalling sites. Nature. 2009;457(7230):736-40. [PubMed: 19079237]
• [58] van Anken E et al. Specificity in endoplasmic reticulumstresssignaling in yeast entails a step-wise engagement ofHAC1 mRNA to clusters of the stress sensor Ire1. eLife. 2014;3:e05031. [PubMed: 25549299]
• [59] Yanagitani K et al. Cotranslational targeting of XBP1 protein tothe membrane promotes cytoplasmic splicing of its own mRNA.Mol Cell. 2009; 34(2):191-200. [PubMed: 19394296]
• [60] Lee AS Hendershot LM. ER-stress and cancer. Cancer Biol Ther.2006; 5(7):721-2. [PubMed: 16880733]
• [61] Carrara M et al. Noncanonical binding of BiP ATPase domain toIre1 and Perk is dissociated by unfolded protein CH1 to initiateER-stress signaling. eLife. 2015; 4:03522 [PubMed: 25692299]
• [62] Bertolotti A et al. Dynamic interaction of BiP and ER-stresstransducers in the unfolded-protein response. Nat Cell Biol.2000; 2(6):326-32. [PubMed: 10854322]
• [63] Anelli T et al. Sequential steps and checkpoints in the earlyexocytic compartment during secretory IgM biogenesis. EMBOJ. 2007; 26(19):4177-88. [PubMed: 17805346]
• [64] Martensson IL Keenan RA Licence S. The pre-B-cell receptor.Curr Opin Immunol. 2007; 19(2):137-42. [PubMed: 17306522]
• [65] Feige MJ Buchner J. Principles and engineering of antibodyfolding and assembly. Biochim Biophys Acta. 2014;1844(11):2024-31. [PubMed: 24931831]
• [66] Hendershot LM Sitia R. Immunoglobulin assembly andsecretion. in: Molecular Biology of B Cells, Honjo T Alt FW andNeuberger MS, Eds. Elsevier Acad Press, Amsterdam. 2005;261–73.
• [67] Shapiro IM et al. Boning up on autophagy: the role ofautophagy in skeletal biology. Autophagy. 2014; 10(1):7-19. [PubMed: 24225636]
• [68] Settembre C et al. Signals from the lysosome: a control centrefor cellular clearance and energy metabolism. Nat Rev Mol CellBiol. 2013; 14(5):283-96. [PubMed: 23609508]
• [69] Pennuto M et al. Ablation of the UPR-mediator CHOP restoresmotor function and reduces demyelination in Charcot-Marie-Tooth 1B mice. Neuron. 2008; 57(3):393-405. [PubMed:18255032]
• [70] Wrabetz L et al. Different intracellular pathomechanismsproduce diverse Myelin Protein Zero neuropathies in transgenicmice. J Neurosci. 2006; 26(8):2358-68. [PubMed: 16495463]
• [71] D’Antonio M et al. Resetting translational homeostasis restoresmyelination in Charcot-Marie-Tooth disease type 1B mice. J ExpMed. 2013; 210(4):821-38. [PubMed: 23547100]
• [72] Das I et al. Preventing proteostasis diseases by selectiveinhibition of a phosphatase regulatory subunit. Science. 2015;348(6231):239-42. [PubMed: 25859045]
• [73] Lomas DA et al. The mechanism of Z alpha 1-antitrypsinaccumulation in the liver. Nature. 1992; 357(6379):605-7. [PubMed: 1608473]
• [74] Bernascone I et al. A transgenic mouse model for uromodulinassociatedkidney diseases shows specific tubulo-interstitialdamage, urinary concentrating defect and renal failure. HumMol Genet. 2010; 19(15):2998-3010. [PubMed: 20472742]
• [75] Lencer WI et al. Innate Immunity at Mucosal Surfaces: theIRE1-RIDD-RIG-I Pathway. Trends Immunol. 2015; [PubMed:26093676]
• [76] Cheng SH et al. Defective intracellular transport and processingof CFTR is the molecular basis of most cystic fibrosis. Cell.1990; 63(4):827-34. [PubMed: 1699669]
• [77] Payne AS Kelly EJ Gitlin JD. Functional expression of the Wilsondisease protein reveals mislocalization and impaired copperdependenttrafficking of the common H1069Q mutation. ProcNatl Acad Sci U S A. 1998; 95(18):10854-9. [PubMed: 9724794]
• [78] Marino M et al. SEPN1, an endoplasmic reticulum-localizedselenoprotein linked to skeletal muscle pathology, counteractshyperoxidation by means of redox-regulating SERCA2 pumpactivity. Hum Mol Genet. 2015; 24(7):1843-55. [PubMed:25452428]
• [79] Bertolotti M et al. Tyrosine kinase signal modulation: a matterof H2O2 membrane permeability? Antioxid Redox Signal. 2013;19(13):1447-51. [PubMed: 23541115]
• [80] Howson R et al. Construction, verification and experimentaluse of two epitope-tagged collections of budding yeast strains.Comp Funct Genomics. 2005; 6(1-2):2-16. [PubMed: 18629296]
• [81] Encell LP et al. Development of a dehalogenase-based proteinfusion tag capable of rapid, selective and covalent attachmentto customizable ligands. Curr Chem Genomics. 2012; 6:55-71. [PubMed: 23248739]
• [82] Hall MP et al. Engineered luciferase reporter from a deep seashrimp utilizing a novel imidazopyrazinone substrate. ACSChem Biol. 2012; 7(11):1848-57. [PubMed: 22894855]
• [83] Nguyen VD et al. Pre-expression of a sulfhydryl oxidasesignificantly increases the yields of eukaryotic disulfide bondcontaining proteins expressed in the cytoplasm of E.coli.Microbial Cell Fact. 2011; 10:1. [Pubmed: 21211066]
• [84] Hatahet F Ruddock LW. Topological plasticity of enzymesinvolved in disulfide bond formation allows catalysis ineither the periplasm or the cytoplasm. J Mol Biol. 2013;425(18):3268-76. [PubMed: 23810903]
• [85] Matos CF et al. Efficient export of prefolded, disulfide-bondedrecombinant proteins to the periplasm by the Tat pathwayin Escherichia coli CyDisCo strains. Biotech Progress. 2014;30(2):281-90. [PubMed: 24376243]

Identifiers

DOI

10.1515/ersc-2015-0006