ER chaperones in mammalian development and human diseases

The field of endoplasmic reticulum (ER) stress in mammalian cells has expanded rapidly during the past decade, contributing to understanding of the molecular pathways that allow cells to adapt to perturbations in ER homeostasis. One major mechanism is mediated by molecular ER chaperones which are critical not only for quality control of proteins processed in the ER, but also for regulation of ER signaling in response to ER stress. Here, we summarized the properties and functions of GRP78/BiP, GRP94/gp96, GRP170/ORP150, GRP58/ERp57, PDI, ERp72, calnexin, calreticulin, EDEM, Herp and co‐chaperones SIL1 and P58IPK and their role in development and diseases. Many of the new insights are derived from recently constructed mouse models where the genes encoding the chaperones are genetically altered, providing invaluable tools for examining the physiological involvement of the ER chaperones in vivo.

[1]  M. Molinari,et al.  Consequences of ERp57 Deletion on Oxidative Folding of Obligate and Facultative Clients of the Calnexin Cycle* , 2006, Journal of Biological Chemistry.

[2]  S. Patierno,et al.  Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions , 2004, Breast Cancer Research and Treatment.

[3]  J. Castilla,et al.  The Disulfide Isomerase Grp58 Is a Protective Factor against Prion Neurotoxicity , 2005, The Journal of Neuroscience.

[4]  Y. Fujinaga.  Transport of bacterial toxins into target cells: pathways followed by cholera toxin and botulinum progenitor toxin. , 2006, Journal of biochemistry.

[5]  G. Stamp,et al.  Early Postnatal Death and Motor Disorders in Mice Congenitally Deficient in Calnexin Expression , 2002, Molecular and Cellular Biology.

[6]  S. Pizzo,et al.  Activation and Cross-talk between Akt, NF-κB, and Unfolded Protein Response Signaling in 1-LN Prostate Cancer Cells Consequent to Ligation of Cell Surface-associated GRP78* , 2006, Journal of Biological Chemistry.

[7]  L. Hendershot,et al.  The ER function BiP is a master regulator of ER function. , 2004, The Mount Sinai journal of medicine, New York.

[8]  A. J. Parodi,et al.  Protein glucosylation and its role in protein folding. , 2000, Annual review of biochemistry.

[9]  N. Sivasubramanian,et al.  Homocysteine Induces Expression and Secretion of Monocyte Chemoattractant Protein-1 and Interleukin-8 in Human Aortic Endothelial Cells: Implications for Vascular Disease , 2001, Circulation.

[10]  H. Ohno,et al.  Cell Surface Expression of Calnexin, a Molecular Chaperone in the Endoplasmic Reticulum* , 2000, The Journal of Biological Chemistry.

[11]  T. Podor,et al.  Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. , 1999, Blood.

[12]  R. Kratzke,et al.  In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid. , 2005, Biochemical and biophysical research communications.

[13]  S. Groshen,et al.  Expression of Stress Response Protein Grp78 Is Associated with the Development of Castration-Resistant Prostate Cancer , 2006, Clinical Cancer Research.

[14]  A. Paetau,et al.  The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone , 2005, Nature Genetics.

[15]  J. Hirsh,et al.  Characterization of the stress-inducing effects of homocysteine. , 1998, The Biochemical journal.

[16]  Yinan Zhang,et al.  Assembly of MHC class I molecules within the endoplasmic reticulum , 2006, Immunologic research.

[17]  H. Wootz,et al.  ER stress and neurodegenerative diseases , 2006, Cell Death and Differentiation.

[18]  R. Ross.  Atherosclerosis is an inflammatory disease , 1999 .

[19]  Takashi Uehara,et al.  S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration , 2006, Nature.

[20]  K. Coser,et al.  The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Amy S. Lee,et al.  Glucose regulated proteins in cancer progression, Drug resistance and immunotherapy , 2006, Cancer biology & therapy.

[22]  W. Lennarz,et al.  Export of a Cysteine-Free Misfolded Secretory Protein from the Endoplasmic Reticulum for Degradation Requires Interaction with Protein Disulfide Isomerase , 1999, The Journal of cell biology.

[23]  R. Austin,et al.  Activation of the Unfolded Protein Response Occurs at All Stages of Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice , 2005, Circulation.

[24]  L. Ruddock,et al.  The human protein disulphide isomerase family: substrate interactions and functional properties , 2005, EMBO reports.

[25]  T Aso,et al.  Homocysteine Induces Programmed Cell Death in Human Vascular Endothelial Cells through Activation of the Unfolded Protein Response* , 2001, The Journal of Biological Chemistry.

[26]  Amy S. Lee,et al.  Endoplasmic Reticulum Stress-induced Apoptosis , 2006, Journal of Biological Chemistry.

[27]  A. Koong,et al.  The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors , 2005, Molecular Cancer Research.

[28]  L. Hendershot,et al.  A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. , 2002, Molecular biology of the cell.

[29]  Amy S. Lee,et al.  Stress induction of GRP78/BiP and its role in cancer. , 2006, Current molecular medicine.

[30]  Marek Michalak,et al.  Calreticulin Differentially Modulates Calcium Uptake and Release in the Endoplasmic Reticulum and Mitochondria* , 2002, The Journal of Biological Chemistry.

[31]  M. Gorospe,et al.  P58IPK, a Novel Endoplasmic Reticulum Stress-inducible Protein and Potential Negative Regulator of eIF2α Signaling* , 2003, The Journal of Biological Chemistry.

[32]  S. Lovell,et al.  ERp57 is essential for efficient folding of glycoproteins sharing common structural domains , 2007, The EMBO journal.

[33]  Amy S. Lee,et al.  In Vivo Regulation of Grp78/BiP Transcription in the Embryonic Heart , 2006, Journal of Biological Chemistry.

[34]  Amy S. Lee.  GRP78 induction in cancer: therapeutic and prognostic implications. , 2007, Cancer research.

[35]  C. Turano,et al.  Proteins of the PDI family: Unpredicted non‐ER locations and functions , 2002, Journal of cellular physiology.

[36]  Zihai Li,et al.  Roles of heat shock protein gp96 in the ER quality control: redundant or unique function? , 2005, Molecules and cells.

[37]  S. Pizzo,et al.  Binding of Activated α2-Macroglobulin to Its Cell Surface Receptor GRP78 in 1-LN Prostate Cancer Cells Regulates PAK-2-dependent Activation of LIMK* , 2005, Journal of Biological Chemistry.

[38]  M. Tohyama,et al.  Role of Herp in the endoplasmic reticulum stress response , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[39]  D. Bredesen,et al.  Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. , 2004, Current opinion in cell biology.

[40]  S. Saga,et al.  Functional characterization of 3 thioredoxin homology domains of ERp72 , 2005, Cell stress & chaperones.

[41]  Mingqing Li,et al.  Underglycosylation of ATF6 as a Novel Sensing Mechanism for Activation of the Unfolded Protein Response* , 2004, Journal of Biological Chemistry.

[42]  Peter Walter,et al.  On the mechanism of sensing unfolded protein in the endoplasmic reticulum. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Yuuki Kawamura,et al.  Endoplasmic Reticulum Stress-inducible Protein, Herp, Enhances Presenilin-mediated Generation of Amyloid β-Protein* 210 , 2002, The Journal of Biological Chemistry.

[44]  T. Sommer,et al.  ERAD: the long road to destruction , 2005, Nature Cell Biology.

[45]  R. Kaufman,et al.  Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation , 2006, The Journal of cell biology.

[46]  S. Groshen,et al.  Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. , 2007, Human pathology.

[47]  K. Krause,et al.  Calreticulin Is Essential for Cardiac Development , 1999, The Journal of cell biology.

[48]  T. Rapoport,et al.  Unfolded cholera toxin is transferred to the ER membrane and released from protein disulfide isomerase upon oxidation by Ero1 , 2002, The Journal of cell biology.

[49]  Toshiharu Suzuki,et al.  Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides. , 2007, The Biochemical journal.

[50]  J. Rothman,et al.  Peptide-binding specificity of the molecular chaperone BiP , 1991, Nature.

[51]  M. Mattson,et al.  Dietary restriction and 2‐deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: Evidence for a preconditioning mechanism , 1999, Journal of neuroscience research.

[52]  P. Reitsma,et al.  Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. , 1996, The New England journal of medicine.

[53]  H. Klamut,et al.  Overexpression of the 78-kDa Glucose-regulated Protein/Immunoglobulin-binding Protein (GRP78/BiP) Inhibits Tissue Factor Procoagulant Activity* , 2003, The Journal of Biological Chemistry.

[54]  G. de Prat-Gay,et al.  UDP-Glc:glycoprotein glucosyltransferase recognizes structured and solvent accessible hydrophobic patches in molten globule-like folding intermediates , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[55]  M. Katze,et al.  Control of PERK eIF2α kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[56]  A. Helenius,et al.  Minor folding defects trigger local modification of glycoproteins by the ER folding sensor GT , 2005, The EMBO journal.

[57]  Yoshiyuki Kaneko,et al.  The Hsp110 and Grp170 stress proteins: newly recognized relatives of the Hsp70s , 2000, Cell stress & chaperones.

[58]  K. Krause,et al.  Functional specialization of calreticulin domains , 2001, The Journal of cell biology.

[59]  S. Bates,et al.  Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. , 2005, Cancer research.

[60]  P. Srivastava.  Therapeutic cancer vaccines. , 2006, Current opinion in immunology.

[61]  L. Ellerby,et al.  Coupling Endoplasmic Reticulum Stress to the Cell Death Program , 2001, The Journal of Biological Chemistry.

[62]  P. Muchowski,et al.  Modulation of neurodegeneration by molecular chaperones , 2005, Nature Reviews Neuroscience.

[63]  W. Diekmann,et al.  Retention and retrieval: both mechanisms cooperate to maintain calreticulin in the endoplasmic reticulum. , 1994, Journal of cell science.

[64]  K. Mori,et al.  Role of Disulfide Bridges Formed in the Luminal Domain of ATF6 in Sensing Endoplasmic Reticulum Stress , 2006, Molecular and Cellular Biology.

[65]  H. Söling,et al.  Reduction of protein disulfide bonds in an oxidizing environment , 1997, FEBS letters.

[66]  Peter Walter,et al.  Inaugural Article: On the mechanism of sensing unfolded protein in the endoplasmic reticulum , 2005 .

[67]  E. Falk,et al.  TDAG51 Is Induced by Homocysteine, Promotes Detachment-mediated Programmed Cell Death, and Contributes to the Development of Atherosclerosis in Hyperhomocysteinemia* , 2003, Journal of Biological Chemistry.

[68]  E. Trombetta,et al.  Calnexin, calreticulin and the folding of glycoproteins. , 1997, Trends in cell biology.

[69]  Zhaohui Xu,et al.  The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response , 2006, Proceedings of the National Academy of Sciences.

[70]  B. E. Black,et al.  Retrotranslocation of the Chaperone Calreticulin from the Endoplasmic Reticulum Lumen to the Cytosol , 2005, Molecular and Cellular Biology.

[71]  Eggleton,et al.  Pathophysiological Roles of Calreticulin in Autoimmune Disease , 1999, Scandinavian journal of immunology.

[72]  J. Castilla,et al.  Perturbation of Endoplasmic Reticulum Homeostasis Facilitates Prion Replication* , 2007, Journal of Biological Chemistry.

[73]  F. Baas,et al.  The unfolded protein response is activated in Alzheimer’s disease , 2005, Acta Neuropathologica.

[74]  M. Michalak,et al.  Endoplasmic reticulum in the heart, a forgotten organelle? , 2001, Molecular and Cellular Biochemistry.

[75]  D. Ron,et al.  Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. , 2001, Molecular cell.

[76]  L. Hendershot,et al.  ER chaperone functions during normal and stress conditions , 2004, Journal of Chemical Neuroanatomy.

[77]  Randal J. Kaufman,et al.  Endoplasmic Reticulum Chaperone Protein GRP78 Protects Cells from Apoptosis Induced by Topoisomerase Inhibitors , 2003, Journal of Biological Chemistry.

[78]  T. Miyata,et al.  Homocysteine-respondent Genes in Vascular Endothelial Cells Identified by Differential Display Analysis , 1996, The Journal of Biological Chemistry.

[79]  Amy S. Lee,et al.  The Endoplasmic Reticulum Chaperone Glycoprotein GRP94 with Ca2+-binding and Antiapoptotic Properties Is a Novel Proteolytic Target of Calpain during Etoposide-induced Apoptosis* , 1999, The Journal of Biological Chemistry.

[80]  C. Hetz,et al.  Stressing out the ER: a role of the unfolded protein response in prion-related disorders. , 2006, Current molecular medicine.

[81]  M. Michalak,et al.  The ins and outs of calreticulin: from the ER lumen to the extracellular space. , 2001, Trends in cell biology.

[82]  Amy S. Lee,et al.  Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[83]  Z. Wang,et al.  Calreticulin expression is associated with androgen regulation of the sensitivity to calcium ionophore-induced apoptosis in LNCaP prostate cancer cells. , 1999, Cancer research.

[84]  Amy S. Lee,et al.  GRP78/BiP Is Required for Cell Proliferation and Protecting the Inner Cell Mass from Apoptosis during Early Mouse Embryonic Development , 2006, Molecular and Cellular Biology.

[85]  J. A. Barnes,et al.  Immunolocalization and heart levels of GRP94 in the mouse during post-implantation development , 1997, Anatomy and Embryology.

[86]  M. Sousa,et al.  Recognition of the oligosaccharide and protein moieties of glycoproteins by the UDP-Glc:glycoprotein glucosyltransferase. , 1992, Biochemistry.

[87]  T. Liu,et al.  Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. , 2001, Life sciences.

[88]  R. Kaufman,et al.  The mammalian unfolded protein response. , 2003, Annual review of biochemistry.

[89]  M. Katze,et al.  Pancreatic (cid:1) -Cell Failure and Diabetes in Mice With a Deletion Mutation of the Endoplasmic Reticulum Molecular Chaperone Gene P58 IPK , 2022 .

[90]  P. Arvan,et al.  Protein disulfide isomerase–like proteins play opposing roles during retrotranslocation , 2006, The Journal of cell biology.

[91]  G. Werstuck,et al.  Hyperhomocysteinemia and its role in the development of atherosclerosis. , 2003, Clinical biochemistry.

[92]  J. Brodsky,et al.  Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). , 2005, Journal of biochemistry.

[93]  M. Katze,et al.  Double-Stranded RNA-Independent Dimerization of Interferon-Induced Protein Kinase PKR and Inhibition of Dimerization by the Cellular P58IPK Inhibitor , 1998, Molecular and Cellular Biology.

[94]  G. Lathrop,et al.  Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. , 2004, Diabetes.

[95]  R. Kratzke,et al.  In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind β-amyloid , 2005 .

[96]  Amy S. Lee,et al.  Transgenic mouse model for monitoring endoplasmic reticulum stress in vivo , 2004, Nature Medicine.

[97]  Marek Michalak,et al.  Contrasting functions of calreticulin and calnexin in glycoprotein folding and ER quality control. , 2004, Molecular cell.

[98]  S. Tuve,et al.  Responses Cyclophosphamide Treatment on Antitumor Immune Expression and Oncolysis in Combination with Low-Dose Effect of Adenovirus-Mediated Heat Shock Protein , 2006 .

[99]  P. Kloetzel,et al.  The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. , 2005, Journal of molecular biology.

[100]  I. Harting,et al.  Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy , 2005, Nature Genetics.

[101]  R. Kaufman,et al.  Persistent glycoprotein misfolding activates the glucosidase II/UGT1-driven calnexin cycle to delay aggregation and loss of folding competence. , 2005, Molecular cell.

[102]  J. Weissman,et al.  The action of molecular chaperones in the early secretory pathway. , 2001, Annual review of genetics.

[103]  P. Reitsma,et al.  Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. , 1996, The New England journal of medicine.

[104]  A. Helenius,et al.  Glycoproteins form mixed disulphides with oxidoreductases during folding in living cells , 1999, Nature.

[105]  J. Whisstock,et al.  AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP , 2006, Nature.

[106]  C. Rodighiero,et al.  Protein Disulfide Isomerase Acts as a Redox-Dependent Chaperone to Unfold Cholera Toxin , 2001, Cell.

[107]  G. Wang,et al.  Homocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radicals. , 2001, The Biochemical journal.

[108]  F. Momburg,et al.  Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57 , 2006, Nature Immunology.

[109]  C. Turano,et al.  Nuclear localization and DNA interaction of protein disulfide isomerase ERp57 in mammalian cells , 2002, Journal of cellular biochemistry.

[110]  Amy S. Lee.  Coordinated regulation of a set of genes by glucose and calcium ionophores in mammalian cells , 1987 .

[111]  S. Groshen,et al.  GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. , 2006, Cancer research.

[112]  Hiderou Yoshida,et al.  A time-dependent phase shift in the mammalian unfolded protein response. , 2003, Developmental cell.

[113]  Yuan-Yuan Shi,et al.  Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. , 2001, The Journal of clinical investigation.

[114]  R. Zimmermann,et al.  The nucleotide exchange factor activity of Grp170 may explain the non‐lethal phenotype of loss of Sil1 function in man and mouse , 2006, FEBS letters.

[115]  R. Ross.  The pathogenesis of atherosclerosis: a perspective for the 1990s , 1993, Nature.

[116]  D. Scheuner,et al.  Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis , 2005, Nature Medicine.

[117]  Toshiyuki Miyata,et al.  Herp, a New Ubiquitin-like Membrane Protein Induced by Endoplasmic Reticulum Stress* , 2000, The Journal of Biological Chemistry.

[118]  C. Koumenis.  ER stress, hypoxia tolerance and tumor progression. , 2006, Current molecular medicine.

[119]  H. Knapp,et al.  Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. , 1999, Circulation.

[120]  David Y. Thomas,et al.  Glycopeptide specificity of the secretory protein folding sensor UDP–glucose glycoprotein:glucosyltransferase , 2003, EMBO reports.

[121]  Toshiharu Suzuki,et al.  Endoplasmic reticulum chaperones inhibit the production of amyloid-β peptides , 2007 .

[122]  J. Castilla,et al.  Caspase‐12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein , 2003, The EMBO journal.

[123]  V. Fuster,et al.  Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. , 1999, Circulation.

[124]  S. Ackerman,et al.  Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP , 2005, Nature Genetics.

[125]  M. Glickman,et al.  A window of opportunity: timing protein degradation by trimming of sugars and ubiquitins. , 2005, Trends in biochemical sciences.

[126]  T. Elliott,et al.  Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin. , 2002, Immunity.

[127]  David Y. Thomas,et al.  The ER protein folding sensor UDP-glucose glycoprotein–glucosyltransferase modifies substrates distant to local changes in glycoprotein conformation , 2004, Nature Structural &Molecular Biology.

[128]  W. Arap,et al.  Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. , 2004, Cancer cell.

[129]  M. Sousa,et al.  The molecular basis for the recognition of misfolded glycoproteins by the UDP‐Glc:glycoprotein glucosyltransferase. , 1995, The EMBO journal.

[130]  David B. Williams,et al.  Functions of ERp57 in the Folding and Assembly of Major Histocompatibility Complex Class I Molecules* , 2006, Journal of Biological Chemistry.

[131]  M. Katze,et al.  P58IPK, a novel cochaperone containing tetratricopeptide repeats and a J-domain with oncogenic potential , 2000, Cellular and Molecular Life Sciences CMLS.

[132]  S. Tanaka,et al.  Up-regulation of Protein-disulfide Isomerase in Response to Hypoxia/Brain Ischemia and Its Protective Effect against Apoptotic Cell Death* , 2000, The Journal of Biological Chemistry.

[133]  Maurizio Molinari,et al.  Role of EDEM in the Release of Misfolded Glycoproteins from the Calnexin Cycle , 2003, Science.

[134]  É. Nadeau,et al.  Escherichia coli: on-farm contamination of animals. , 2006, Revue scientifique et technique.

[135]  Zihai Li,et al.  Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[136]  Amy S. Lee,et al.  The glucose-regulated proteins: stress induction and clinical applications. , 2001, Trends in biochemical sciences.

[137]  R. Clarke,et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease. , 1991, The New England journal of medicine.