The unfolded protein response in metazoan development

ABSTRACT Eukaryotic cells respond to an overload of unfolded proteins in the endoplasmic reticulum (ER) by activating signaling pathways that are referred to as the unfolded protein response (UPR). Much UPR research has been conducted in cultured cells that exhibit no baseline UPR activity until they are challenged by ER stress initiated by chemicals or mutant proteins. At the same time, many genes that mediate UPR signaling are essential for the development of organisms ranging from Drosophila and fish to mice and humans, indicating that there is physiological ER stress that requires UPR in normally developing animal tissues. Recent studies have elucidated the tissue-specific roles of all three branches of UPR in distinct developing tissues of Drosophila, fish and mammals. As discussed in this Review, these studies not only reveal the physiological functions of the UPR pathways but also highlight a surprising degree of specificity associated with each UPR branch in development. Summary: We review evidence that normally developing tissues have physiological ER stress, and the three branches of the unfolded protein response (UPR) exhibit a high level of specificity in promoting their development.

[1]  C. Hetz,et al.  The Unfolded Protein Response and Cell Fate Control. , 2017, Molecular cell.

[2]  S. Tsang,et al.  The unfolded protein response regulator ATF6 promotes mesodermal differentiation , 2018, Science Signaling.

[3]  Albert J R Heck,et al.  Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. , 2003, Immunity.

[4]  Ying Cao,et al.  Xenopus X-box binding protein 1, a leucine zipper transcription factor, is involved in the BMP signaling pathway. , 2003, Developmental biology.

[5]  Hiderou Yoshida,et al.  Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. , 2007, Developmental cell.

[6]  Kezhong Zhang,et al.  The unfolded protein response transducer IRE1α prevents ER stress‐induced hepatic steatosis , 2011, EMBO Journal.

[7]  D. Scheuner,et al.  The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. , 2005, The Journal of clinical investigation.

[8]  R. Kaufman,et al.  Physiological/pathological ramifications of transcription factors in the unfolded protein response , 2017, Genes & development.

[9]  Barbara C. McGrath,et al.  The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones , 2018, The Journal of Biological Chemistry.

[10]  B. Ueberheide,et al.  The GCN2-ATF4 Signaling Pathway Induces 4E-BP to Bias Translation and Boost Antimicrobial Peptide Synthesis in Response to Bacterial Infection. , 2017, Cell reports.

[11]  K. Rajewsky,et al.  Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1 , 2003, Nature Immunology.

[12]  R. Faure,et al.  A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott–Rallison syndrome , 2006, Clinical genetics.

[13]  H. Orr.  An unfolded protein , 2001, The Lancet.

[14]  D. Ron,et al.  Xbp1-independent Ire1 signaling is required for photoreceptor differentiation and rhabdomere morphogenesis in Drosophila. , 2013, Cell reports.

[15]  D. Thuerauf,et al.  Opposing Roles for ATF6α and ATF6β in Endoplasmic Reticulum Stress Response Gene Induction* , 2004, Journal of Biological Chemistry.

[16]  Huiyu Xu,et al.  ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver. , 2015, Blood.

[17]  F. Urano,et al.  Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. , 2000, Science.

[18]  A. Volchuk,et al.  Pancreatic β-cells depend on basal expression of active ATF6α-p50 for cell survival even under nonstress conditions. , 2012, American journal of physiology. Cell physiology.

[19]  D. Ron,et al.  Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase , 1999, Nature.

[20]  N. Zhang,et al.  4E-BP is a target of the GCN2–ATF4 pathway during Drosophila development and aging , 2017, The Journal of cell biology.

[21]  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.

[22]  Judy H. Cho,et al.  Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. , 2001, The Journal of clinical investigation.

[23]  D. Ron,et al.  The requirement of IRE1 and XBP1 in resolving physiological stress during Drosophila development , 2017, Journal of Cell Science.

[24]  Peter Walter,et al.  Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase , 1993, Cell.

[25]  H. Ryoo,et al.  PERK Limits Drosophila Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress , 2015, PLoS genetics.

[26]  R. Kaufman,et al.  A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. , 1998, Genes & development.

[27]  D. Hebert,et al.  Protein folding in the endoplasmic reticulum. , 2013, Cold Spring Harbor perspectives in biology.

[28]  K. Mori,et al.  Vertebrate unfolded protein response: mammalian signaling pathways are conserved in Medaka fish. , 2011, Cell structure and function.

[29]  G. Hummer,et al.  Activation of the Unfolded Protein Response by Lipid Bilayer Stress. , 2017, Molecular cell.

[30]  D. Ron,et al.  Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains , 2013, Proceedings of the National Academy of Sciences.

[31]  H. Aburatani,et al.  ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress. , 2008, Cell metabolism.

[32]  H. Ryoo,et al.  Drosophila XBP1 Expression Reporter Marks Cells under Endoplasmic Reticulum Stress and with High Protein Secretory Load , 2013, PloS one.

[33]  R. Wek,et al.  Dimerization and Release of Molecular Chaperone Inhibition Facilitate Activation of Eukaryotic Initiation Factor-2 Kinase in Response to Endoplasmic Reticulum Stress* , 2002, The Journal of Biological Chemistry.

[34]  Hao Li,et al.  The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis , 2012, eLife.

[35]  K. Mori,et al.  Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response. , 2001, The Biochemical journal.

[36]  Patrick B. F. O'Connor,et al.  Translation of 5′ leaders is pervasive in genes resistant to eIF2 repression , 2015, eLife.

[37]  S. Shenolikar,et al.  Growth Arrest and DNA Damage-Inducible Protein GADD34 Assembles a Novel Signaling Complex Containing Protein Phosphatase 1 and Inhibitor 1 , 2001, Molecular and Cellular Biology.

[38]  C. Atreya,et al.  BMC Cell Biology , 2007 .

[39]  I. Dawid,et al.  Coordinated activation of the secretory pathway during notochord formation in the Xenopus embryo , 2009, Development.

[40]  T. Townes,et al.  Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. , 2002, Blood.

[41]  Peichuan Zhang,et al.  The PERK Eukaryotic Initiation Factor 2α Kinase Is Required for the Development of the Skeletal System, Postnatal Growth, and the Function and Viability of the Pancreas , 2002, Molecular and Cellular Biology.

[42]  Anna Skorczyk-Werner,et al.  Achromatopsia mutations target sequential steps of ATF6 activation , 2016, Proceedings of the National Academy of Sciences.

[43]  Yumei Li,et al.  ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement. , 2015, Investigative ophthalmology & visual science.

[44]  K. Mori,et al.  Endoplasmic Reticulum Stress-Induced Formation of Transcription Factor Complex ERSF Including NF-Y (CBF) and Activating Transcription Factors 6α and 6β That Activates the Mammalian Unfolded Protein Response , 2001, Molecular and Cellular Biology.

[45]  D. Scheuner,et al.  Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. , 2009, Cell metabolism.

[46]  G. Lathrop,et al.  EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome , 2000, Nature Genetics.

[47]  T. Todo,et al.  Unfolded protein response transducer IRE1-mediated signaling independent of XBP1 mRNA splicing is not required for growth and development of medaka fish , 2017, eLife.

[48]  Y. Kimata,et al.  Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways , 2011, Molecular biology of the cell.

[49]  T. Iwawaki,et al.  IRE1α Disruption Causes Histological Abnormality of Exocrine Tissues, Increase of Blood Glucose Level, and Decrease of Serum Immunoglobulin Level , 2010, PloS one.

[50]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[51]  S. Akira,et al.  Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres , 1998, Genes to cells : devoted to molecular & cellular mechanisms.

[52]  Taro L. Saito,et al.  ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish , 2013, Molecular biology of the cell.

[53]  J. Leiden,et al.  Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor. , 2000, Developmental biology.

[54]  E McEwen,et al.  Translational control is required for the unfolded protein response and in vivo glucose homeostasis. , 2001, Molecular cell.

[55]  D. Ron,et al.  Stress‐induced gene expression requires programmed recovery from translational repression , 2003, The EMBO journal.

[56]  Jonathan S Weissman,et al.  Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response , 2006, Science.

[57]  Gerald C. Chu,et al.  XBP‐1 is required for biogenesis of cellular secretory machinery of exocrine glands , 2005, The EMBO journal.

[58]  Stevan R. Hubbard,et al.  IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA , 2002, Nature.

[59]  J. Miyazaki,et al.  IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells , 2018, The Journal of cell biology.

[60]  K. Mori,et al.  Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. , 1999, Molecular biology of the cell.

[61]  Masahiko Kuroda,et al.  Cloning of mammalian Ire1 reveals diversity in the ER stress responses , 1998, The EMBO journal.

[62]  R. Schekman,et al.  In vitro reconstitution of ER-stress induced ATF6 transport in COPII vesicles , 2009, Proceedings of the National Academy of Sciences.

[63]  R. Wek,et al.  Phosphorylation of eIF2 Facilitates Ribosomal Bypass of an Inhibitory Upstream ORF to Enhance CHOP Translation*♦ , 2011, The Journal of Biological Chemistry.

[64]  D. Ron,et al.  Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response , 2004, The Journal of cell biology.

[65]  D. Nomura,et al.  The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms. , 2018, Developmental cell.

[66]  S. Orkin,et al.  An essential role in liver development for transcription factor XBP-1. , 2000, Genes & development.

[67]  T. W. Fawcett,et al.  Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. , 1999, The Biochemical journal.

[68]  Anne Bertolotti,et al.  Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response , 2000, Nature Cell Biology.

[69]  A. Hinnebusch,et al.  Translational control by 5′-untranslated regions of eukaryotic mRNAs , 2016, Science.

[70]  Hiderou Yoshida,et al.  ATF6 Activated by Proteolysis Binds in the Presence of NF-Y (CBF) Directly to the cis-Acting Element Responsible for the Mammalian Unfolded Protein Response , 2000, Molecular and Cellular Biology.

[71]  I. Litvan,et al.  Tauopathy‐associated PERK alleles are functional hypomorphs that increase neuronal vulnerability to ER stress , 2018, Human molecular genetics.

[72]  S. Beck,et al.  Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia , 2015, Nature Genetics.

[73]  Neal N. Iwakoshi,et al.  Plasma cell differentiation requires the transcription factor XBP-1 , 2001, Nature.

[74]  Donghui Zhou,et al.  Phosphorylation of eIF2 Directs ATF5 Translational Control in Response to Diverse Stress Conditions* , 2008, Journal of Biological Chemistry.

[75]  Sounak Gupta,et al.  PERK (EIF2AK3) Regulates Proinsulin Trafficking and Quality Control in the Secretory Pathway , 2010, Diabetes.

[76]  H. Hoover,et al.  Coordination of ATF6-mediated Transcription and ATF6 Degradation by a Domain That Is Shared with the Viral Transcription Factor, VP16* , 2002, The Journal of Biological Chemistry.

[77]  R. Sood,et al.  Translational Control -subunit Kinase, Pek, Involved in Α Pancreatic Eukaryotic Initiation Factor 2 Identification and Characterization Of , 1998 .

[78]  D. Ron,et al.  Inhibition of a constitutive translation initiation factor 2α phosphatase, CReP, promotes survival of stressed cells , 2003, The Journal of cell biology.

[79]  L. Glimcher,et al.  Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes , 2004, Science.

[80]  P. Walter,et al.  A Novel Mechanism for Regulating Activity of a Transcription Factor That Controls the Unfolded Protein Response , 1996, Cell.

[81]  Anna Skorczyk-Werner,et al.  Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene , 2017, European Journal of Human Genetics.

[82]  Andrew J. Lees,et al.  Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy , 2011, Nature Genetics.

[83]  A. Schier,et al.  Nodal signaling activates differentiation genes during zebrafish gastrulation. , 2007, Developmental biology.

[84]  Robert W. Williams,et al.  Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals , 2017, The Journal of cell biology.

[85]  M. Schapira,et al.  Regulated translation initiation controls stress-induced gene expression in mammalian cells. , 2000, Molecular cell.

[86]  S. Yamanaka,et al.  Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability , 2009, Proceedings of the National Academy of Sciences.

[87]  J. W. Brewer,et al.  Activation of an Unfolded Protein Response during Differentiation of Antibody-secreting B Cells* , 2002, The Journal of Biological Chemistry.

[88]  J. Sambrook,et al.  A transmembrane protein with a cdc2+ CDC28 -related kinase activity is required for signaling from the ER to the nucleus , 1993, Cell.

[89]  Randal J. Kaufman,et al.  Complementary Signaling Pathways Regulate the Unfolded Protein Response and Are Required for C. elegans Development , 2001, Cell.

[90]  R. Wek,et al.  Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[91]  H. Steller,et al.  Unfolded protein response in a Drosophila model for retinal degeneration , 2007, The EMBO journal.

[92]  P. Walter,et al.  Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. , 1996, The EMBO journal.

[93]  The integrated stress response regulates BMP signalling through effects on translation , 2018, BMC Biology.

[94]  X. Chen,et al.  ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. , 2000, Molecular cell.

[95]  J. Shendure,et al.  Mutation of ATF6 causes autosomal recessive achromatopsia , 2015, Human Genetics.