Quality control mechanisms of protein biogenesis: proteostasis dies hard

Timothy Jan Bergmann; Giorgia Brambilla Pisoni; Maurizio Molinari; Timothy Jan Bergmann; Giorgia Brambilla Pisoni; Maurizio Molinari

doi:10.3934/biophy.2016.4.456

AIMS Biophysics

2016, Volume 3, Issue 4: 456-478. doi: 10.3934/biophy.2016.4.456

Previous Article Next Article

Review

Quality control mechanisms of protein biogenesis: proteostasis dies hard

1.
Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
2.
Università della Svizzera italiana (USI), Lugano, Switzerland
3.
Eidgenössische technische Hochschule Zürich (ETHZ), Departement Biologie (DBIOL), Zurich, Switzerland
4.
Ecole polytechnique de Lausanne (EPFL), Lausanne, Switzerland

Received: 16 September 2016 Accepted: 12 October 2016 Published: 24 October 2016

The biosynthesis of proteins entails a complex series of chemical reactions that transform the information stored in the nucleic acid sequence into a polypeptide chain that needs to properly fold and reach its functional location in or outside the cell. It is of no surprise that errors might occur that alter the polypeptide sequence leading to a non-functional proteins or that impede delivery of proteins at the appropriate site of activity. In order to minimize such mistakes and guarantee the synthesis of the correct amount and quality of the proteome, cells have developed folding, quality control, degradation and transport mechanisms that ensure and tightly regulate protein biogenesis. Genetic mutations, harsh environmental conditions or attack by pathogens can subvert the cellular quality control machineries and perturb cellular proteostasis leading to pathological conditions. This review summarizes basic concepts of the flow of information from DNA to folded and active proteins and to the variable fidelity (from incredibly high to quite sloppy) characterizing these processes. We will give particular emphasis on events that maintain or recover the homeostasis of the endoplasmic reticulum (ER), a major site of proteins synthesis and folding in eukaryotic cells. Finally, we will report on how cells can adapt to stressful conditions, how perturbation of ER homeostasis may result in diseases and how these can be treated.
- protein synthesis,
- translation,
- folding,
- quality control,
- ER-associated degradation (ERAD),
- autophagy,
- unfolded protein response (UPR),
- central dogma,
- CAT-tails,
- proteostasis,
- conformational (protein misfolding) diseases,
- chemical and pharmacological chaperones
Citation: Timothy Jan Bergmann, Giorgia Brambilla Pisoni, Maurizio Molinari. Quality control mechanisms of protein biogenesis: proteostasis dies hard[J]. AIMS Biophysics, 2016, 3(4): 456-478. doi: 10.3934/biophy.2016.4.456

Related Papers:

Abstract

The biosynthesis of proteins entails a complex series of chemical reactions that transform the information stored in the nucleic acid sequence into a polypeptide chain that needs to properly fold and reach its functional location in or outside the cell. It is of no surprise that errors might occur that alter the polypeptide sequence leading to a non-functional proteins or that impede delivery of proteins at the appropriate site of activity. In order to minimize such mistakes and guarantee the synthesis of the correct amount and quality of the proteome, cells have developed folding, quality control, degradation and transport mechanisms that ensure and tightly regulate protein biogenesis. Genetic mutations, harsh environmental conditions or attack by pathogens can subvert the cellular quality control machineries and perturb cellular proteostasis leading to pathological conditions. This review summarizes basic concepts of the flow of information from DNA to folded and active proteins and to the variable fidelity (from incredibly high to quite sloppy) characterizing these processes. We will give particular emphasis on events that maintain or recover the homeostasis of the endoplasmic reticulum (ER), a major site of proteins synthesis and folding in eukaryotic cells. Finally, we will report on how cells can adapt to stressful conditions, how perturbation of ER homeostasis may result in diseases and how these can be treated.

References

[1]	Crick FHC (1956) Ideas on protein synthesis. Wellcome Library for the History and Understanding of Medicine. Avaiable from: http://archives.wellcome.ac.uk/.
[2]	Crick FHC (1970) Central Dogma of Molecular Biology. Nature 227: 561–563. doi: 10.1038/227561a0
[3]	Baltimore D (1970) RNA-dependent DNA polymerase in virions of RNA tumour viruses. Nature 226: 1209–1211. doi: 10.1038/2261209a0
[4]	Temin HM, Mizutani S (1970) RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 226: 1211–1213. doi: 10.1038/2261211a0
[5]	Koonin EV (2012) Does the central dogma still stand? Biol Direct 7: 27. doi: 10.1186/1745-6150-7-27
[6]	Melnikov S, Ben-Shem A, Garreau de Loubresse N, et al. (2012) One core, two shells: bacterial and eukaryotic ribosomes. Nat Struct Mol Biol 19: 560–567. doi: 10.1038/nsmb.2313
[7]	Khatter H, Myasnikov AG, Natchiar SK, et al. (2015) Structure of the human 80S ribosome. Nature 520: 640–645. doi: 10.1038/nature14427
[8]	Kolitz SE, Lorsch JR (2010) Eukaryotic initiator tRNA: finely tuned and ready for action. FEBS Lett 584: 396–404. doi: 10.1016/j.febslet.2009.11.047
[9]	Rodnina MV (2016) The ribosome in action: Tuning of translational efficiency and protein folding. Protein Sci 25: 1390–1406. doi: 10.1002/pro.2950
[10]	Dabrowski M, Bukowy-Bieryllo Z, Zietkiewicz E (2015) Translational readthrough potential of natural termination codons in eucaryotes--The impact of RNA sequence. RNA Biol 12: 950–958. doi: 10.1080/15476286.2015.1068497
[11]	Karpinets TV, Greenwood DJ, Sams CE, et al. (2006) RNA:protein ratio of the unicellular organism as a characteristic of phosphorous and nitrogen stoichiometry and of the cellular requirement of ribosomes for protein synthesis. BMC Biol 4: 1–10. doi: 10.1186/1741-7007-4-1
[12]	Ingolia NT, Lareau LF, Weissman JS (2011) Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147: 789–802. doi: 10.1016/j.cell.2011.10.002
[13]	Dennis PP, Bremer H (1974) Differential Rate of Ribosomal Protein Synthesis in Escherichia coli B/r. J Mol Biol 84: 407–422. doi: 10.1016/0022-2836(74)90449-5
[14]	Dennis PP, Nomura M (1974) Stringent Control of Ribosomal Protein Gene Expression in Escherichia coli. Proc Nat Acad Sci USA 71: 3819–3823. doi: 10.1073/pnas.71.10.3819
[15]	Young R, Bremer H (1976) Polypeptide-Chain-Elongation Rate in Escherichia coli B/r as a Function ofGrowth Rate. Biochem J 160: 185–194. doi: 10.1042/bj1600185
[16]	Schaaper RM (1993) Base selection, proofreading, and mismatch repair during DNA replication in Escherichia coli. J Biol Chem 268: 23762–23765.
[17]	Drake JW, Charlesworth B, Charlesworth D, et al. (1998) Rates of spontaneous mutation. Genetics 148: 1667–1686.
[18]	Kunkel TA (2004) DNA replication fidelity. J Biol Chem 279: 16895–16898. doi: 10.1074/jbc.R400006200
[19]	Bebenek K, Kunkel TA (2004) Functions of DNA polymerases. Adv Protein Chem 69: 137–165. doi: 10.1016/S0065-3233(04)69005-X
[20]	Kunkel TA (2009) Evolving Views of DNA Replication (In)Fidelity. Cold Spring Harb Sym 74: 91–101. doi: 10.1101/sqb.2009.74.027
[21]	Sainsbury S, Bernecky C, Cramer P (2015) Structural basis of transcription initiation by RNA polymerase II. Nat Rev Mol Cell Biol 16: 129–143. doi: 10.1038/nrm3952
[22]	Sharma N (2016) Regulation of RNA polymerase II-mediated transcriptional elongation: Implications in human disease. IUBMB Life 68: 709–716. doi: 10.1002/iub.1538
[23]	Loya TJ, Reines D (2016) Recent advances in understanding transcription termination by RNA polymerase II. F1000 Res 5: 1478.
[24]	Schwanhausser B, Busse D, Li N, et al. (2011) Global quantification of mammalian gene expression control. Nature 473: 337–342. doi: 10.1038/nature10098
[25]	Imashimizu M, Oshima T, Lubkowska L, et al. (2013) Direct assessment of transcription fidelity by high-resolution RNA sequencing. Nucleic Acids Res 41: 9090–9104. doi: 10.1093/nar/gkt698
[26]	Ninio J (1991) Connections between translation, transcription and replication error-rates. Biochimie 73: 1517–1523. doi: 10.1016/0300-9084(91)90186-5
[27]	Gouta JF, Thomasb WK, Smithc Z, et al. (2013) Large-scale detection of in vivo transcription errors. PNAS 110: 18584–18589. doi: 10.1073/pnas.1309843110
[28]	Cochella L, Green R (2005) Fidelity in protein synthesis. Curr Biol 15: 536–540. doi: 10.1016/j.cub.2005.02.019
[29]	Kramer EB, Farabaugh PJ (2007) The frequency of translational misreading errors in E. coli is largely determined by tRNA competition. RNA 13: 87–96.
[30]	Zaher HS, Green R (2009) Fidelity at the molecular level: lessons from protein synthesis. Cell 136: 746–762. doi: 10.1016/j.cell.2009.01.036
[31]	Gingold H, Pilpel Y (2011) Determinants of translation efficiency and accuracy. Mol Syst Biol 7: 141–150.
[32]	Ribas de Pouplana L, Santos MA, Zhu JH, et al. (2014) Protein mistranslation: friend or foe? Trends Biochem Sci 39: 355–362. doi: 10.1016/j.tibs.2014.06.002
[33]	Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181: 223–230. doi: 10.1126/science.181.4096.223
[34]	Bulik S, Peters B, Holzhutter HG (2005) Quantifying the Contribution of Defective Ribosomal Products to Antigen Production: A Model-Based Computational Analysis. J Immunol 175: 7957–7964. doi: 10.4049/jimmunol.175.12.7957
[35]	Vabulas RM, Hartl FU (2005) Protein synthesis upon acute nutrient restriction relies on proteasome function. Science 310: 1960–1963. doi: 10.1126/science.1121925
[36]	Schubert U, Antón LC, Gibbs J, et al. (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404: 770–774. doi: 10.1038/35008096
[37]	Vabulas RM, Hartl UF (2005) Protein Synthesis upon Acute Nutrient Restriction Relies on Proteasome Function. Science 310: 1960–1963. doi: 10.1126/science.1121925
[38]	Hung MC, Link W (2011) Protein localization in disease and therapy. J Cell Sci 124: 3381–3392.
[39]	Chacinska A, Koehler CM, Milenkovic D, et al. (2009) Importing mitochondrial proteins: machineries and mechanisms. Cell 138: 628–644. doi: 10.1016/j.cell.2009.08.005
[40]	Rapoport TA (2007) Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature 450: 663–669. doi: 10.1038/nature06384
[41]	Geva Y, Schuldiner M (2014) The back and forth of cargo exit from the endoplasmic reticulum. Curr Biol 24: 130–136. doi: 10.1016/j.cub.2013.12.008
[42]	Barlowe C, Helenius A (2016) Cargo Capture and Bulk Flow in the Early Secretory Pathway. Annu Rev Cell Dev Biol 32: 197–222. doi: 10.1146/annurev-cellbio-111315-125016
[43]	Herrmann JM, Neupert W (2000) Protein transport into mitochondria. Curr Opin Microbiol 3: 210–214. doi: 10.1016/S1369-5274(00)00077-1
[44]	Zimmermann R, Eyrisch S, Ahmad M, et al. (2011) Protein translocation across the ER membrane. Biochim Biophys Acta 1808: 912–924. doi: 10.1016/j.bbamem.2010.06.015
[45]	Freitas N, Cunha C (2009) Mechanisms and signals for the nuclear import of proteins. Curr Genomics 10: 550–557. doi: 10.2174/138920209789503941
[46]	Nichols WC, Seligsohn U, Zivelin A, et al. (1998) Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell 93: 61–70. doi: 10.1016/S0092-8674(00)81146-0
[47]	Spreafico M, Peyvandi F (2009) Combined Factor V and Factor VIII Deficiency. Semin Thromb Hemost 35: 390–399. doi: 10.1055/s-0029-1225761
[48]	Rock KL, Gramm C, Rothstein L, et al. (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78: 761–771. doi: 10.1016/S0092-8674(94)90462-6
[49]	Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426: 895–899. doi: 10.1038/nature02263
[50]	Finley D (2009) Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem 78: 477–513. doi: 10.1146/annurev.biochem.78.081507.101607
[51]	Rock KL, Farfan-Arribas DJ, Colbert JD, et al. (2014) Re-examining class-I presentation and the DRiP hypothesis. Trends Immunol 35: 144–152. doi: 10.1016/j.it.2014.01.002
[52]	Cohen-Kaplan V, Livneh I, Avni N, et al. (2016) The ubiquitin-proteasome system and autophagy: Coordinated and independent activities. Int J Biochem Cell Biol: In Press.
[53]	Ravikumar B, Sarkar S, Davies JE, et al. (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90: 1383–1435. doi: 10.1152/physrev.00030.2009
[54]	Mariappan M, Li X, Stefanovic S, et al. (2010) A ribosome-associating factor chaperones tail-anchored membrane proteins. Nature 466: 1120–1124. doi: 10.1038/nature09296
[55]	Brandman O, Stewart-Ornstein J, Wong D, et al. (2012) A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell 151: 1042–1054. doi: 10.1016/j.cell.2012.10.044
[56]	Defenouillère Q, Yao Y, Mouaikel J, et al. (2013) Cdc48 associated complex bound to 60s particles is required for the clearance of aberrant translation products. PNAS 110: 5046–5051. doi: 10.1073/pnas.1221724110
[57]	Shao S, von der Malsburg K, Hegde RS (2013) Listerin-dependent nascent protein ubiquitination relies on ribosome subunit dissociation. Mol Cell 50: 637–648. doi: 10.1016/j.molcel.2013.04.015
[58]	Verma R, Oania RS, Kolawa1 NJ, et al. (2013) Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. eLife 2: e00308.
[59]	Shen PS, Park J, Qin Y, et al. (2016) Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science 347: 75–78.
[60]	Ghaemmaghami S, Huh WK, Bower K, et al. (2003) Global analysis of protein expression in yeast. Nature 425: 737–741. doi: 10.1038/nature02046
[61]	Schwarz F, Aebi M (2011) Mechanisms and principles of N-linked protein glycosylation. Curr Opin Struct Biol 21: 576–582. doi: 10.1016/j.sbi.2011.08.005
[62]	Tannous A, Pisoni GB, Hebert DN, et al. (2015) N-linked sugar-regulated protein folding and quality control in the ER. Semin Cell Dev Biol 41: 79–89. doi: 10.1016/j.semcdb.2014.12.001
[63]	Ellgaard L, Molinari M, Helenius A (1999) Setting the standards: quality control in the secretory pathway. Science 286: 1882–1888. doi: 10.1126/science.286.5446.1882
[64]	Aebi M, Bernasconi R, Clerc S, et al. (2010) N-glycan structures: recognition and processing in the ER. Trends Biochem Sci 35: 74–82. doi: 10.1016/j.tibs.2009.10.001
[65]	Schallus T, Feher K, Sternberg U, et al. (2010) Analysis of the specific interactions between the lectin domain of malectin and diglucosides. Glycobiology 20: 1010–1020. doi: 10.1093/glycob/cwq059
[66]	Galli C, Bernasconi R, Solda T, et al. (2011) Malectin participates in a backup glycoprotein quality control pathway in the mammalian ER. PLoS One 6: e16304. doi: 10.1371/journal.pone.0016304
[67]	Pisoni GB, Ruddock LW, Bulleid N, et al. (2015) Division of labor among oxidoreductases: TMX1 preferentially acts on transmembrane polypeptides. Mol Biol Cell 26: 3390–3400. doi: 10.1091/mbc.E15-05-0321
[68]	Lamriben L, Graham JB, Adams BM, et al. (2016) N-Glycan-based ER Molecular Chaperone and Protein Quality Control System: The Calnexin Binding Cycle. Traffic 17: 308–326. doi: 10.1111/tra.12358
[69]	Cabral CM, Choudhury P, Liu Y, et al. (2000) Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J Biol Chem 275: 25015–25022. doi: 10.1074/jbc.M910172199
[70]	Olivari S, Cali T, Salo KE, et al. (2006) EDEM1 regulates ER-associated degradation by accelerating de-mannosylation of folding-defective polypeptides and by inhibiting their covalent aggregation. Biochem Biophys Res Commun 349: 1278–1284. doi: 10.1016/j.bbrc.2006.08.186
[71]	Ninagawa S, Okada T, Sumitomo Y, et al. (2014) EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step. J Cell Biol 206: 347–356. doi: 10.1083/jcb.201404075
[72]	Hirao K, Natsuka Y, Tamura T, et al. (2006) EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J Biol Chem 281: 9650–9658. doi: 10.1074/jbc.M512191200
[73]	Olivari S, Molinari M (2007) Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. FEBS Lett 581: 3658–3664. doi: 10.1016/j.febslet.2007.04.070
[74]	Christianson JC, Shaler TA, Tyler RE, et al. (2008) OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nat Cell Biol 10: 272–282. doi: 10.1038/ncb1689
[75]	Bernasconi R, Galli C, Calanca V, et al. (2010) Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. J Cell Biol 188: 223–235. doi: 10.1083/jcb.200910042
[76]	Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9: 944–957. doi: 10.1038/nrm2546
[77]	Merulla J, Solda T, Molinari M (2015) A novel UGGT1 and p97-dependent checkpoint for native ectodomains with ionizable intramembrane residue. Mol Biol Cell 26: 1532–1542. doi: 10.1091/mbc.E14-12-1615
[78]	Merulla J, Fasana E, Solda T, et al. (2013) Specificity and regulation of the endoplasmic reticulum-associated degradation machinery. Traffic 14: 767–777. doi: 10.1111/tra.12068
[79]	Bernasconi R, Molinari M (2011) ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER. Curr Opin Cell Biol 23: 176–183. doi: 10.1016/j.ceb.2010.10.002
[80]	Koenig PA, Nicholls PK, Schmidt FI, et al. (2014) The E2 ubiquitin-conjugating enzyme UBE2J1 is required for spermiogenesis in mice. J Biol Chem 289: 34490–34502. doi: 10.1074/jbc.M114.604132
[81]	Hagiwara M, Ling J, Koenig PA, et al. (2016) Posttranscriptional Regulation of Glycoprotein Quality Control in the Endoplasmic Reticulum Is Controlled by the E2 Ub-Conjugating Enzyme UBC6e. Mol Cell 63: 753–767. doi: 10.1016/j.molcel.2016.07.014
[82]	Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221: 3–12. doi: 10.1002/path.2697
[83]	Mizushima N, Ohsumi Y, Yoshimori T (2002) Autophagosome Formation in Mammalian Cells. Cell Struct Funct 27: 421–429. doi: 10.1247/csf.27.421
[84]	Ohsumi Y (2014) Historical landmarks of autophagy research. Cell Res 24: 9–23. doi: 10.1038/cr.2013.169
[85]	Ariosa AR, Klionsky DJ (2016) Autophagy core machinery: overcoming spatial barriers in neurons. J Mol Med (Berl): In Press.
[86]	Ryter SW, Cloonan SM, Choi AM (2013) Autophagy: a critical regulator of cellular metabolism and homeostasis. Mol Cells 36: 7–16. doi: 10.1007/s10059-013-0140-8
[87]	Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368: 1845–1846. doi: 10.1056/NEJMc1303158
[88]	Lin F, Qin ZH (2013) Degradation of misfolded proteins by autophagy: is it a strategy for Huntington's disease treatment? J Huntingtons Dis 2: 149–157.
[89]	Webb JL, Ravikumar B, Atkins J, et al. (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278: 25009–25013. doi: 10.1074/jbc.M300227200
[90]	Pickford F, Masliah E, Britschgi M, 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 Invest 118: 2190–2199.
[91]	Lee MJ, Lee JH, Rubinsztein DC (2013) Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog Neurobiol 105: 49–59. doi: 10.1016/j.pneurobio.2013.03.001
[92]	Perlmutter DH (2011) Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med 62: 333–345. doi: 10.1146/annurev-med-042409-151920
[93]	Fu L, Sztul E (2009) ER-associated complexes (ERACs) containing aggregated cystic fibrosis transmembrane conductance regulator (CFTR) are degraded by autophagy. Eur J Cell Biol 88: 215–226. doi: 10.1016/j.ejcb.2008.11.003
[94]	Farre JC, Subramani S (2016) Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat Rev Mol Cell Biol 17: 537–552.
[95]	Khaminets A, Heinrich T, Mari M, et al. (2015) Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522: 354–358. doi: 10.1038/nature14498
[96]	Fumagalli FNJ, Bergmann TJ, Cebollero E, et al. (2016) Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat Cell Biol: In press.
[97]	Inoue T, Tsai B (2013) How viruses use the endoplasmic reticulum for entry, replication, and assembly. Cold Spring Harb Perspect Biol 5: a013250. doi: 10.1101/cshperspect.a013250
[98]	van den Boomen DJ, Lehner PJ (2015) Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I. Mol Immunol 68: 106–111. doi: 10.1016/j.molimm.2015.07.005
[99]	Gardner BM, Pincus D, Gotthardt K, et al. (2013) Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol 5: a013169.
[100]	Mori K (2009) Signalling pathways in the unfolded protein response: development from yeast to mammals. J Biochem 146: 743–750. doi: 10.1093/jb/mvp166
[101]	Zhang L, Zhang C, Wang A (2016) Divergence and Conservation of the Major UPR Branch IRE1-bZIP Signaling Pathway across Eukaryotes. Sci Rep 6: 27362. doi: 10.1038/srep27362
[102]	Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23: 7448–7459. doi: 10.1128/MCB.23.21.7448-7459.2003
[103]	Hollien J, Weissman JS (2006) Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313: 104–107. doi: 10.1126/science.1129631
[104]	Haze K, Yoshida H, Yanagi H, et al. (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: 3787–3799. doi: 10.1091/mbc.10.11.3787
[105]	Shoulders MD, Ryno LM, Genereux JC, et al. (2013) Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 3: 1279–1292. doi: 10.1016/j.celrep.2013.03.024
[106]	Bertolotti A, Zhang Y, Hendershot LM, et al. (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2: 326–332. doi: 10.1038/35014014
[107]	Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397: 271–274. doi: 10.1038/16729
[108]	Vattem KM, Wek RC (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A 101: 11269–11274. doi: 10.1073/pnas.0400541101
[109]	Lu PD, Harding HP, Ron D (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 167: 27–33. doi: 10.1083/jcb.200408003
[110]	Jiang HY, Wek SA, McGrath BC, et al. (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 24: 1365–1377. doi: 10.1128/MCB.24.3.1365-1377.2004
[111]	Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569: 29–63. doi: 10.1016/j.mrfmmm.2004.06.056
[112]	Redler RL, Das J, Diaz JR, et al. (2016) Protein Destabilization as a Common Factor in Diverse Inherited Disorders. J Mol Evol 82: 11–16. doi: 10.1007/s00239-015-9717-5
[113]	Sitia R, Braakman I (2003) Quality control in the endoplasmic reticulum protein factory. Nature 426: 891–894. doi: 10.1038/nature02262
[114]	Bernier V, Lagace M, Bichet DG, et al. (2004) Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 15: 222–228. doi: 10.1016/j.tem.2004.05.003
[115]	Molinari M (2007) N-glycan structure dictates extension of protein folding or onset of disposal. Nat Chem Biol 3: 313–320. doi: 10.1038/nchembio880
[116]	Kopito RR, Ron D (2000) Conformational disease. Nat Cell Biol 2: 207–209. doi: 10.1038/35041139
[117]	Gidalevitz T, Ben-Zvi A, Ho KH, et al. (2006) Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311: 1471–1474. doi: 10.1126/science.1124514
[118]	Powers ET, Morimoto RI, Dillin A, et al. (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78: 959–991. doi: 10.1146/annurev.biochem.052308.114844
[119]	Morello JP, Petaja-Repo UE, Bichet DG, et al. (2000) Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21: 466–469. doi: 10.1016/S0165-6147(00)01575-3
[120]	Cohen FE, Kelly JW (2003) Therapeutic approaches to protein-misfolding diseases. Nature 426: 905–909. doi: 10.1038/nature02265
[121]	Convertino M, Das J, Dokholyan NV (2016) Pharmacological Chaperones: Design and Development of New Therapeutic Strategies for the Treatment of Conformational Diseases. ACS Chem Biol 11: 1471–1489. doi: 10.1021/acschembio.6b00195
[122]	Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4: 966–977. doi: 10.1038/nrc1505
[123]	Fernandez PM, Tabbara SO, Jacobs LK, et al. (2000) Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat 59: 15–26. doi: 10.1023/A:1006332011207
[124]	Shuda M, Kondoh N, Imazeki N, et al. (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38: 605–614.
[125]	Song MS, Park YK, Lee JH, et al. (2001) Induction of glucose-regulated protein 78 by chronic hypoxia in human gastric tumor cells through a protein kinase C-epsilon/ERK/AP-1 signaling cascade. Cancer Res 61: 8322–8330.
[126]	Gazit G, Lu J, Lee AS (1999) De-regulation of GRP stress protein expression in human breast cancer cell lines. Breast Cancer Res Treat 54: 135–146. doi: 10.1023/A:1006102411439
[127]	Plate L, Paxman RJ, Wiseman RL, et al. (2016) Modulating protein quality control. Elife 5: e18431.
[128]	Wang X, Venable J, LaPointe P, et al. (2006) Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127: 803–815. doi: 10.1016/j.cell.2006.09.043
[129]	Mu TW, Ong DS, Wang YJ, et al. (2008) Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134: 769–781. doi: 10.1016/j.cell.2008.06.037
[130]	Chiang WC, Hiramatsu N, Messah C, et al. (2012) Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation. Invest Ophthalmol Vis Sci 53: 7159–7166. doi: 10.1167/iovs.12-10222
[131]	Luheshi LM, Dobson CM (2009) Bridging the gap: from protein misfolding to protein misfolding diseases. FEBS Lett 583: 2581–2586. doi: 10.1016/j.febslet.2009.06.030
[132]	Braakman I, Bulleid NJ (2011) Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem 80: 71–99. doi: 10.1146/annurev-biochem-062209-093836
[133]	Brodsky JL, Skach WR (2011) Protein folding and quality control in the endoplasmic reticulum: Recent lessons from yeast and mammalian cell systems. Curr Opin Cell Biol 23: 464–475. doi: 10.1016/j.ceb.2011.05.004
[134]	Papa FR, Zhang C, Shokat K, et al. (2003) Bypassing a kinase activity with an ATP-competitive drug. Science 302: 1533–1537. doi: 10.1126/science.1090031
[135]	Wiseman RL, Zhang Y, Lee KP, et al. (2010) Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1. Mol Cell 38: 291–304. doi: 10.1016/j.molcel.2010.04.001
[136]	Wang L, Perera BG, Hari SB, et al. (2012) Divergent allosteric control of the IRE1alpha endoribonuclease using kinase inhibitors. Nat Chem Biol 8: 982–989. doi: 10.1038/nchembio.1094
[137]	Sidrauski C, Tsai JC, Kampmann M, et al. (2015) Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. Elife 4: e07314.
[138]	Robblee MM, Kim CC, Porter Abate J, et al. (2016) Saturated Fatty Acids Engage an IRE1alpha-Dependent Pathway to Activate the NLRP3 Inflammasome in Myeloid Cells. Cell Rep 14: 2611–2623. doi: 10.1016/j.celrep.2016.02.053
[139]	Gallagher CM, Walter P (2016) Ceapins inhibit ATF6alpha signaling by selectively preventing transport of ATF6alpha to the Golgi apparatus during ER stress. Elife 5: e11880.
[140]	Gallagher CM, Garri C, Cain EL, et al. (2016) Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6alpha branch. Elife 5: e11880.
[141]	Plate L, Cooley CB, Chen JJ, et al. (2016) Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. Elife 5: e15550.
[142]	Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157: 1262–1278. doi: 10.1016/j.cell.2014.05.010

Reader Comments

Your name:*

Email:*
© 2016 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)