Current Genetics

, Volume 65, Issue 2, pp 467–471 | Cite as

(Un)folding mechanisms of adaptation to ER stress: lessons from aneuploidy

  • Carine Beaupere
  • Vyacheslav M. LabunskyyEmail author


During stress, accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers activation of the adaptive mechanisms that restore protein homeostasis. One mechanism that eukaryotic cells use to respond to ER stress is through activation of the unfolded protein response (UPR) signaling pathway, which initiates degradation of misfolded proteins and leads to inhibition of translation and increased expression of chaperones and oxidative folding components that enhance ER protein folding capacity. However, the mechanisms of adaptation to ER stress are not limited to the UPR. Using yeast Saccharomyces cerevisiae, we recently discovered that the protein folding burden in the ER can be alleviated in a UPR-independent manner through duplication of whole chromosomes containing ER stress-protective genes. Here we discuss our findings and their implication to our understanding of the mechanisms by which cells respond to protein misfolding in the ER.


Aneuploidy Genome instability Next-generation sequencing ER stress resistance Unfolded protein response 



This work was supported by the National Institutes of Health Grant AG054566 (to VML). This research was conducted while VML was an AFAR Research Grant recipient from the American Federation for Aging Research.


  1. Barnes G, Hansen WJ, Holcomb CL, Rine J (1984) Asparagine-linked glycosylation in Saccharomyces cerevisiae: genetic analysis of an early step. Mol Cell Biol 4(11):2381–2388CrossRefGoogle Scholar
  2. Beaupere C et al (2018) Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast. Proc Natl Acad Sci USA 115(38):9586–9591CrossRefGoogle Scholar
  3. Bretthauer RK (2009) Structure, expression, and regulation of UDP-GlcNAc: dolichol phosphate GlcNAc-1-phosphate transferase (DPAGT1). Curr Drug Targets 10(6):477–482CrossRefGoogle Scholar
  4. Chawla A, Chakrabarti S, Ghosh G, Niwa M (2011) Attenuation of yeast UPR is essential for survival and is mediated by IRE1 kinase. J Cell Biol 193(1):41–50CrossRefGoogle Scholar
  5. Chen G, Bradford WD, Seidel CW, Li R (2012) Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482(7384):246–250CrossRefGoogle Scholar
  6. Defenouillere Q, Fromont-Racine M (2017) The ribosome-bound quality control complex: from aberrant peptide clearance to proteostasis maintenance. Curr Genet 63(6):997–1005CrossRefGoogle Scholar
  7. Denzel MS, et al (2014) Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156(6):1167–1178CrossRefGoogle Scholar
  8. Dephoure N et al (2014) Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. eLife 3:e03023CrossRefGoogle Scholar
  9. Finley D, Chen X, Walters KJ (2016) Gates, channels, and switches: elements of the proteasome machine. Trends Biochem Sci 41(1):77–93CrossRefGoogle Scholar
  10. Gardner BM, Pincus D, Gotthardt K, Gallagher CM, Walter P (2013) Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol 5(3):a013169CrossRefGoogle Scholar
  11. Giaever G et al (1999) Genomic profiling of drug sensitivities via induced haploinsufficiency. Nat Genet 21(3):278–283CrossRefGoogle Scholar
  12. Gottschling DE, Nystrom T (2017) The upsides and downsides of organelle interconnectivity. Cell 169(1):24–34CrossRefGoogle Scholar
  13. Groll M et al (1999) The catalytic sites of 20S proteasomes and their role in subunit maturation: a mutational and crystallographic study. Proc Natl Acad Sci USA 96(20):10976–10983CrossRefGoogle Scholar
  14. Helenius A, Aebi M (2004) Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73:1019–1049CrossRefGoogle Scholar
  15. Karagoz GE et al (2017) An unfolded protein-induced conformational switch activates mammalian IRE1. eLife 6:e30700CrossRefGoogle Scholar
  16. Kaya A et al (2015) Adaptive aneuploidy protects against thiol peroxidase deficiency by increasing respiration via key mitochondrial proteins. Proc Natl Acad Sci USA 112(34):10685–10690CrossRefGoogle Scholar
  17. Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10(2):205–215CrossRefGoogle Scholar
  18. Koike N, Hatano Y, Ushimaru T (2018) Heat shock transcriptional factor mediates mitochondrial unfolded protein response. Curr Genet 64(4):907–917CrossRefGoogle Scholar
  19. Labunskyy VM et al (2014) Lifespan extension conferred by endoplasmic reticulum secretory pathway deficiency requires induction of the unfolded protein response. PLoS Genet 10(1):e1004019CrossRefGoogle Scholar
  20. Lennon K, Bird A, Chen YF, Pretel R, Kukuruzinska MA (1997) The dual role of mRNA half-lives in the expression of the yeast ALG7 gene. Mol Cell Biochem 169(1–2):95–106CrossRefGoogle Scholar
  21. Livneh I, Cohen-Kaplan V, Cohen-Rosenzweig C, Avni N, Ciechanover A (2016) The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell Res 26(8):869–885CrossRefGoogle Scholar
  22. Oromendia AB, Dodgson SE, Amon A (2012) Aneuploidy causes proteotoxic stress in yeast. Genes Dev 26(24):2696–2708CrossRefGoogle Scholar
  23. Pavelka N et al (2010) Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468(7321):321–325CrossRefGoogle Scholar
  24. Pereira T et al (2018) Quantitative operating principles of yeast metabolism during adaptation to heat stress. Cell Rep 22(9):2421–2430CrossRefGoogle Scholar
  25. Pincus D et al (2010) BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol 8(7):e1000415CrossRefGoogle Scholar
  26. Selmecki A, Forche A, Berman J (2006) Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313(5785):367–370CrossRefGoogle Scholar
  27. Stauffer B, Powers T (2017) Target of rapamycin signaling mediates vacuolar fragmentation. Curr Genet 63(1):35–42CrossRefGoogle Scholar
  28. Sunshine AB et al (2015) The fitness consequences of aneuploidy are driven by condition-dependent gene effects. PLoS Biol 13(5):e1002155CrossRefGoogle Scholar
  29. Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13(3):184–190CrossRefGoogle Scholar
  30. Torres EM et al (2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317(5840):916–924CrossRefGoogle Scholar
  31. Travers KJ et al (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101(3):249–258CrossRefGoogle Scholar
  32. Van Dalfsen KM et al (2018) Global proteome remodeling during ER stress involves Hac1-driven expression of long undecoded transcript isoforms. Dev Cell 46(2):219–235 (e218) CrossRefGoogle Scholar
  33. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086CrossRefGoogle Scholar
  34. Weimer S et al (2014) d-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat Commun 5:3563CrossRefGoogle Scholar
  35. Yona AH et al (2012) Chromosomal duplication is a transient evolutionary solution to stress. Proc Natl Acad Sci USA 109(51):21010–21015CrossRefGoogle Scholar
  36. Yoshida H (2007) ER stress and diseases. FEBS J 274(3):630–658CrossRefGoogle Scholar
  37. Zhu J, Tsai HJ, Gordon MR, Li R (2018) Cellular stress associated with aneuploidy. Dev Cell 44(4):420–431CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of DermatologyBoston University School of MedicineBostonUSA

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