Advertisement

Neurochemical Research

, Volume 36, Issue 7, pp 1198–1211 | Cite as

Ca2+-Signaling, Alternative Splicing and Endoplasmic Reticulum Stress Responses

  • Joachim KrebsEmail author
  • Jody Groenendyk
  • Marek Michalak
Original Paper

Abstract

Ca2+-signaling, alternative splicing, and stress responses by the endoplasmic reticulum are three important cellular activities which can be strongly interconnected to alter the expression of protein isoforms in a tissue dependent manner or during development depending on the environmental conditions. This integrated network of signaling pathways permits a high degree of versatility and adaptation to metabolic, developmental and stress processes. Defects in its regulation may lead to cellular malfunction.

Keywords

Ca2+-signaling Alternative splicing Stress response UPR BiP/GRP78 ATF6 PERK IRE1 XBP1 

Abbreviations

ASK1

Apoptosis signal regulating kinase 1

ATF

Activating transcription factor

BiP

Ig heavy chain binding protein

CAMKIV

Calmodulin-dependent kinase IV

CHOP

C/EBP homologous protein

CREB

cAMP/Ca2+-responsive element binding protein

EDEM

ER degradation enhancing mannosidase

ER

Endoplasmic reticulum

ERAD

ER-associated degradation

ERSE

ER stress element

GRP

Glucose regulated protein

IKK

IκB kinase

IP3

1,4,5-Inositol triphosphate

IP3R

IP3 receptor

IRE1

Inositol requiring transmembrane kinase/endonuclease 1

JNK

c-jun amino-terminal kinase

NFAT

Nuclear factor activating T-cells

PERK

dsRNA-activated protein kinase-like ER kinase

PMCA

Plasma mebrane calcium ATPase

RYR

Ryanodine receptor

SERCA

Sarco/endoplasmic reticulum calcium ATPase

slo

Slowpoke

STREX

Stress axis-regulated exon

TRAF2

TNF receptor associated factor 2

UPR

Unfolded protein response

UPRE

UPR element

XBP1

X-box binding protein 1

XBP1s

Spliced isoform of X-box binding protein 1

Notes

Acknowledgments

Supported by grants to M.M. from the Canadian Institutes of Health Research (CIHR) (MOP-53050, MOP-15415, MOP-15291) and Alberta Innovates-Health Solutions (AI-HS). The present work was supported by the Max Planck Society.

References

  1. 1.
    Costa FF (2010) Non-coding RNAs: meet thy masters. Bioessays 32(7):599–608PubMedGoogle Scholar
  2. 2.
    Blencowe BJ (2006) Alternative splicing: new insights from global analyses. Cell 126(1):37–47PubMedGoogle Scholar
  3. 3.
    Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336PubMedGoogle Scholar
  4. 4.
    Wang ET, Sandberg R, Luo S et al (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456(7221):470–476PubMedGoogle Scholar
  5. 5.
    Pan Q, Shai O, Lee LJ et al (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40(12):1413–1415PubMedGoogle Scholar
  6. 6.
    Lynch KW (2007) Regulation of alternative splicing by signal transduction pathways. Adv Exp Med Biol 623:161–174PubMedGoogle Scholar
  7. 7.
    Shin C, Manley JL (2004) Cell signalling and the control of pre-mRNA splicing. Nat Rev Mol Cell Biol 5(9):727–738PubMedGoogle Scholar
  8. 8.
    Ip JY, Tong A, Pan Q et al (2007) Global analysis of alternative splicing during T-cell activation. RNA 13(4):563–572PubMedGoogle Scholar
  9. 9.
    Faustino NA, Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev 17(4):419–437PubMedGoogle Scholar
  10. 10.
    Novoyatleva T, Tang Y, Rafalska I et al (2006) Pre-mRNA missplicing as a cause of human disease. Prog Mol Subcell Biol 44:27–46PubMedGoogle Scholar
  11. 11.
    Licatalosi DD, Darnell RB (2006) Splicing regulation in neurologic disease. Neuron 52(1):93–101PubMedGoogle Scholar
  12. 12.
    Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4(7):517–529PubMedGoogle Scholar
  13. 13.
    Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11(4):372–380PubMedGoogle Scholar
  14. 14.
    Kawasaki H, Nakayama S, Kretsinger RH (1998) Classification and evolution of EF-hand proteins. Biometals 11(4):277–295PubMedGoogle Scholar
  15. 15.
    Krebs J, Heizmann CW (2007) Calcium-binding proteins and the EF-hand principle. In: Krebs J, Michalak M (eds) Calcium: a matter of life or death. Elsevier B.V, Amsterdam, The Netherlands, pp 51–93Google Scholar
  16. 16.
    Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89(4):1341–1378PubMedGoogle Scholar
  17. 17.
    Pedersen PL (2007) Transport ATPases into the year 2008: a brief overview related to types, structures, functions and roles in health and disease. J Bioenerg Biomembr 39(5–6):349–355PubMedGoogle Scholar
  18. 18.
    Strehler EE, Strehler-Page MA, Vogel G et al (1989) mRNAs for plasma membrane calcium pump isoforms differing in their regulatory domain are generated by alternative splicing that involves two internal donor sites in a single exon. Proc Natl Acad Sci USA 86(18):6908–6912PubMedGoogle Scholar
  19. 19.
    Strehler EE, Zacharias DA (2001) Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiol Rev 81(1):21–50PubMedGoogle Scholar
  20. 20.
    Zacharias DA, Kappen C (1999) Developmental expression of the four plasma membrane calcium ATPase (Pmca) genes in the mouse. Biochim Biophys Acta 1428(2–3):397–405PubMedGoogle Scholar
  21. 21.
    Stauffer TP, Guerini D, Carafoli E (1995) Tissue distribution of the four gene products of the plasma membrane Ca2+ pump. A study using specific antibodies. J Biol Chem 270(20):12184–12190PubMedGoogle Scholar
  22. 22.
    Stauffer TP, Hilfiker H, Carafoli E et al (1993) Quantitative analysis of alternative splicing options of human plasma membrane calcium pump genes. J Biol Chem 268(34):25993–26003PubMedGoogle Scholar
  23. 23.
    Kosk-Kosicka D, Bzdega T (1988) Activation of the erythrocyte Ca2+-ATPase by either self-association or interaction with calmodulin J. Biol Chem 263:18184–18189Google Scholar
  24. 24.
    Brodin P, Falchetto R, Vorherr T et al (1992) Identification of two domains which mediate the binding of activating phospholipids to the plasma-membrane Ca2+ pump. Eur J Biochem 204(2):939–946PubMedGoogle Scholar
  25. 25.
    James PH, Pruschy M, Vorherr TE et al (1989) Primary structure of the cAMP-dependent phosphorylation site of the plasma membrane calcium pump. Biochemistry 28(10):4253–4258PubMedGoogle Scholar
  26. 26.
    James P, Maeda M, Fischer R et al (1988) Identification and primary structure of a calmodulin binding domain of the Ca2+ pump of human erythrocytes. J Biol Chem 263(6):2905–2910PubMedGoogle Scholar
  27. 27.
    Falchetto R, Vorherr T, Brunner J et al (1991) The plasma membrane Ca2+ pump contains a site that interacts with its calmodulin-binding domain. J Biol Chem 266(5):2930–2936PubMedGoogle Scholar
  28. 28.
    Falchetto R, Vorherr T, Carafoli E (1992) The calmodulin-binding site of the plasma membrane Ca2+ pump interacts with the transduction domain of the enzyme. Protein Sci 1(12):1613–1621PubMedGoogle Scholar
  29. 29.
    Guerini D, Krebs J, Carafoli E (1984) Stimulation of the purified erythrocyte Ca2+ -ATPase by tryptic fragments of calmodulin. J Biol Chem 259(24):15172–15177PubMedGoogle Scholar
  30. 30.
    Enyedi A, Verma AK, Heim R et al (1994) The Ca2+ affinity of the plasma membrane Ca2+ pump is controlled by alternative splicing. J Biol Chem 269(1):41–43PubMedGoogle Scholar
  31. 31.
    Elshorst B, Hennig M, Forsterling H et al (1999) NMR solution structure of a complex of calmodulin with a binding peptide of the Ca2+ pump. Biochemistry 38(38):12320–12332PubMedGoogle Scholar
  32. 32.
    Di Leva F, Domi T, Fedrizzi L et al (2008) The plasma membrane Ca2+ ATPase of animal cells: structure, function and regulation. Arch Biochem Biophys 476(1):65–74PubMedGoogle Scholar
  33. 33.
    Verma AK, Filoteo AG, Stanford DR et al (1988) Complete primary structure of a human plasma membrane Ca2+ pump. J Biol Chem 263(28):14152–14159PubMedGoogle Scholar
  34. 34.
    Shull GE, Greeb J (1988) Molecular cloning of two isoforms of the plasma membrane Ca2+ -transporting ATPase from rat brain. Structural and functional domains exhibit similarity to Na + , K+ - and other cation transport ATPases. J Biol Chem 263(18):8646–8657PubMedGoogle Scholar
  35. 35.
    Guerini D, Garcia-Martin E, Gerber A et al (1999) The expression of plasma membrane Ca2+ pump isoforms in cerebellar granule neurons is modulated by Ca2+. J Biol Chem 274(3):1667–1676PubMedGoogle Scholar
  36. 36.
    Preiano BS, Guerini D, Carafoli E (1996) Expression and functional characterization of isoforms 4 of the plasma membrane calcium pump. Biochemistry 35(24):7946–7953PubMedGoogle Scholar
  37. 37.
    Keeton TP, Burk SE, Shull GE (1993) Alternative splicing of exons encoding the calmodulin-binding domains and C termini of plasma membrane Ca(2 +)-ATPase isoforms 1, 2, 3, and 4. J Biol Chem 268(4):2740–2748PubMedGoogle Scholar
  38. 38.
    Brandt P, Neve RL (1992) Expression of plasma membrane calcium-pumping ATPase mRNAs in developing rat brain and adult brain subregions: evidence for stage-specific expression. J Neurochem 59(4):1566–1569PubMedGoogle Scholar
  39. 39.
    Carafoli E, Stauffer T (1994) The plasma membrane calcium pump: functional domains, regulation of the activity, and tissue specificity of isoform expression. J Neurobiol 25(3):312–324PubMedGoogle Scholar
  40. 40.
    Talarico EF Jr, Mangini NJ (2007) Alternative splice variants of plasma membrane calcium-ATPases in human corneal epithelium. Exp Eye Res 85(6):869–879PubMedGoogle Scholar
  41. 41.
    Xiong Y, Antalffy G, Enyedi A et al (2009) Apical localization of PMCA2w/b is lipid raft-dependent. Biochem Biophys Res Commun 384(1):32–36PubMedGoogle Scholar
  42. 42.
    Blencowe BJ (2000) Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci 25(3):106–110PubMedGoogle Scholar
  43. 43.
    Fairbrother WG, Yeh RF, Sharp PA et al (2002) Predictive identification of exonic splicing enhancers in human genes. Science 297(5583):1007–1013PubMedGoogle Scholar
  44. 44.
    Andreadis A, Gallego ME, Nadal-Ginard B (1987) Generation of protein isoform diversity by alternative splicing: mechanistic and biological implications. Annu Rev Cell Biol 3:207–242PubMedGoogle Scholar
  45. 45.
    Smith CW, Nadal-Ginard B (1989) Mutually exclusive splicing of alpha-tropomyosin exons enforced by an unusual lariat branch point location: implications for constitutive splicing. Cell 56(5):749–758PubMedGoogle Scholar
  46. 46.
    Sheng M, McFadden G, Greenberg ME (1990) Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron 4(4):571–582PubMedGoogle Scholar
  47. 47.
    Matthews RP, Guthrie CR, Wailes LM et al (1994) Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. Mol Cell Biol 14(9):6107–6116PubMedGoogle Scholar
  48. 48.
    Enslen H, Sun P, Brickey D et al (1994) Characterization of Ca2+/calmodulin-dependent protein kinase IV. Role in transcriptional regulation. J Biol Chem 269(22):15520–15527PubMedGoogle Scholar
  49. 49.
    Sheng M, Thompson MA, Greenberg ME (1991) CREB: a Ca(2 +)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252(5011):1427–1430PubMedGoogle Scholar
  50. 50.
    Sun Z, Sassone-Corsi P, Means AR (1995) Calspermin gene transcription is regulated by two cyclic AMP response elements contained in an alternative promoter in the calmodulin kinase IV gene. Mol Cell Biol 15(1):561–571PubMedGoogle Scholar
  51. 51.
    Sun P, Lou L, Maurer RA (1996) Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca2+/calmodulin-dependent protein kinases type I, II, and IV. J Biol Chem 271(6):3066–3073PubMedGoogle Scholar
  52. 52.
    Pognonec P, Boulukos KE, Gesquiere JC et al (1988) Mitogenic stimulation of thymocytes results in the calcium-dependent phosphorylation of c-ets-1 proteins. EMBO J 7(4):977–983PubMedGoogle Scholar
  53. 53.
    Fisher CL, Ghysdael J, Cambier JC (1991) Ligation of membrane Ig leads to calcium-mediated phosphorylation of the proto-oncogene product, Ets-1. J Immunol 146(6):1743–1749PubMedGoogle Scholar
  54. 54.
    Krebs J (1998) Calmodulin-dependent protein kinase IV: regulation of function and expression. Biochim Biophys Acta 1448(2):183–189PubMedGoogle Scholar
  55. 55.
    Krebs J, Means RL, Honegger P (1996) Induction of calmodulin kinase IV by the thyroid hormone during the development of rat brain. J Biol Chem 271(19):11055–11058PubMedGoogle Scholar
  56. 56.
    Liu YY, Brent GA (2002) A complex deoxyribonucleic acid response element in the rat Ca(2 +)/calmodulin-dependent protein kinase IV gene 5’-flanking region mediates thyroid hormone induction and chicken ovalbumin upstream promoter transcription factor 1 repression. Mol Endocrinol 16(11):2439–2451PubMedGoogle Scholar
  57. 57.
    Xie J, Black DL (2001) A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature 410(6831):936–939PubMedGoogle Scholar
  58. 58.
    Xie J, Jan C, Stoilov P et al (2005) A consensus CaMK IV-responsive RNA sequence mediates regulation of alternative exons in neurons. RNA 11(12):1825–1834PubMedGoogle Scholar
  59. 59.
    Lee JA, Xing Y, Nguyen D et al (2007) Depolarization and CaM kinase IV modulate NMDA receptor splicing through two essential RNA elements. PLoS Biol 5(2):e40PubMedGoogle Scholar
  60. 60.
    Krebs J (2009) The influence of calcium signaling on the regulation of alternative splicing. Biochim Biophys Acta 1793(6):979–984PubMedGoogle Scholar
  61. 61.
    Xie J (2008) Control of alternative pre-mRNA splicing by Ca(++) signals. Biochim Biophys Acta 1779(8):438–452PubMedGoogle Scholar
  62. 62.
    Lagrutta A, Shen KZ, North RA et al (1994) Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium-activated potassium channel. J Biol Chem 269(32):20347–20351PubMedGoogle Scholar
  63. 63.
    Tseng-Crank J, Foster CD, Krause JD et al (1994) Cloning, expression, and distribution of functionally distinct Ca(2 +)-activated K+ channel isoforms from human brain. Neuron 13(6):1315–1330PubMedGoogle Scholar
  64. 64.
    Colomer J, Means AR (2007) Physiological roles of the Ca2+/CaM-dependent protein kinase cascade in health and disease. Subcell Biochem 45:169–214PubMedGoogle Scholar
  65. 65.
    Shepard PJ, Hertel KJ (2008) Conserved RNA secondary structures promote alternative splicing. RNA 14(8):1463–1469PubMedGoogle Scholar
  66. 66.
    Yu J, Hai Y, Liu G et al (2009) The heterogeneous nuclear ribonucleoprotein L is an essential component in the Ca2+/calmodulin-dependent protein kinase IV-regulated alternative splicing through cytidine-adenosine repeats. J Biol Chem 284(3):1505–1513PubMedGoogle Scholar
  67. 67.
    Hui J, Hung LH, Heiner M et al (2005) Intronic CA-repeat and CA-rich elements: a new class of regulators of mammalian alternative splicing. EMBO J 24(11):1988–1998PubMedGoogle Scholar
  68. 68.
    Kessler F, Falchetto R, Heim R et al (1992) Study of calmodulin binding to the alternatively spliced C-terminal domain of the plasma membrane Ca2+ pump. Biochemistry 31(47):11785–11792PubMedGoogle Scholar
  69. 69.
    Bland CS, Wang ET, Vu A et al. (2010) Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res 38:7651–7664Google Scholar
  70. 70.
    Guerini D, Wang X, Li L et al (2000) Calcineurin controls the expression of isoform 4CII of the plasma membrane Ca(2 +) pump in neurons. J Biol Chem 275(5):3706–3712PubMedGoogle Scholar
  71. 71.
    Mikoshiba K (2007) IP3 receptor/Ca2+ channel: from discovery to new signaling concepts. J Neurochem 102(5):1426–1446PubMedGoogle Scholar
  72. 72.
    Nakagawa T, Okano H, Furuichi T et al (1991) The subtypes of the mouse inositol 1, 4, 5-trisphosphate receptor are expressed in a tissue-specific and developmentally specific manner. Proc Natl Acad Sci USA 88(14):6244–6248PubMedGoogle Scholar
  73. 73.
    Nucifora FC Jr, Li SH, Danoff S et al (1995) Molecular cloning of a cDNA for the human inositol 1, 4, 5-trisphosphate receptor type 1, and the identification of a third alternatively spliced variant. Brain Res Mol Brain Res 32(2):291–296PubMedGoogle Scholar
  74. 74.
    Choi JY, Beaman-Hall CM, Vallano ML (2004) Granule neurons in cerebellum express distinct splice variants of the inositol trisphosphate receptor that are modulated by calcium. Am J Physiol Cell Physiol 287(4):C971–C980PubMedGoogle Scholar
  75. 75.
    Rossi D, Simeoni I, Micheli M et al (2002) RyR1 and RyR3 isoforms provide distinct intracellular Ca2+ signals in HEK 293 cells. J Cell Sci 115(Pt 12):2497–2504PubMedGoogle Scholar
  76. 76.
    Futatsugi A, Kuwajima G, Mikoshiba K (1995) Tissue-specific and developmentally regulated alternative splicing in mouse skeletal muscle ryanodine receptor mRNA. Biochem J 305(Pt 2):373–378PubMedGoogle Scholar
  77. 77.
    Takasawa S, Kuroki M, Nata K et al. (2010) A novel ryanodine receptor expressed in pancreatic islets by alternative splicing from type 2 ryanodine receptor gene. Biochem Biophys Res Commun 397(2):140–145Google Scholar
  78. 78.
    Leeb T, Brenig B (1998) cDNA cloning and sequencing of the human ryanodine receptor type 3 (RYR3) reveals a novel alternative splice site in the RYR3 gene. FEBS Lett 423(3):367–370PubMedGoogle Scholar
  79. 79.
    Schroder M (2008) Endoplasmic reticulum stress responses. Cell Mol Life Sci 65(6):862–894PubMedGoogle Scholar
  80. 80.
    Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569(1–2):29–63PubMedGoogle Scholar
  81. 81.
    Rao RV, Poksay KS, Castro-Obregon S et al (2004) Molecular components of a cell death pathway activated by endoplasmic reticulum stress. J Biol Chem 279(1):177–187PubMedGoogle Scholar
  82. 82.
    Meldolesi J, Pozzan T (1998) The endoplasmic reticulum Ca2+ store: a view from the lumen. Trends Biochem Sci 23:10–14PubMedGoogle Scholar
  83. 83.
    Corbett EF, Michalak M (2000) Calcium, a signaling molecule in the endoplasmic reticulum? Trends Biochem Sci 25(7):307–311PubMedGoogle Scholar
  84. 84.
    Corbett EF, Michalak KM, Oikawa K et al (2000) The conformation of calreticulin is influenced by the endoplasmic reticulum lumenal environment. J Biol Chem 275:27177–27185PubMedGoogle Scholar
  85. 85.
    Booth C, Koch GEL (1989) Perturbation of cellular calcium induces secretion of luminal ER proteins. Cell 59:729–737PubMedGoogle Scholar
  86. 86.
    Lodish HF, Kong N (1990) Perturbation of cellular calcium blocks exit of secretory proteins from the rough endoplasmic reticulum. J Biol Chem 265:10893–10899PubMedGoogle Scholar
  87. 87.
    Lodish HF, Kong N, Wikstrom L (1992) Calcium is required for folding of newly made subunits of the asialoglycoprotein receptor within the endoplasmic reticulum. J Biol Chem 267:12753–12760PubMedGoogle Scholar
  88. 88.
    Molinari M, Helenius A (2000) Chaperone selection during glycoprotein translocation into the endoplasmic reticulum. Science 288(5464):331–333PubMedGoogle Scholar
  89. 89.
    Meunier L, Usherwood YK, Chung KT et al (2002) A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol Biol Cell 13(12):4456–4469PubMedGoogle Scholar
  90. 90.
    Argon Y, Simen BB (1999) GRP94, an ER chaperone with protein and peptide binding properties. Semin Cell Dev Biol 10(5):495–505PubMedGoogle Scholar
  91. 91.
    Mengesdorf T, Althausen S, Oberndorfer I et al (2001) Response of neurons to an irreversible inhibition of endoplasmic reticulum Ca(2 +)-ATPase: relationship between global protein synthesis and expression and translation of individual genes. Biochem J 356(Pt 3):805–812PubMedGoogle Scholar
  92. 92.
    Koyasu S, Nishida E, Miyata Y et al. (1989) HSP100, a 100-kDa heat shock protein, is a Ca2+-calmodulin-regulated actin-binding protein. J Biol Chem 264(25):15083–15087Google Scholar
  93. 93.
    Mao C, Wang M, Luo B et al. (2010) Targeted mutation of the mouse Grp94 gene disrupts development and perturbs endoplasmic reticulum stress signaling. PLoS One 5(5):e10852Google Scholar
  94. 94.
    Li WW, Alexandre S, Cao X et al. (1993) Transactivation of the grp78 promoter by Ca2+ depletion. A comparative analysis with A23187 and the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. J Biol Chem 268(16):12003–12009Google Scholar
  95. 95.
    Csermely P, Miyata Y, Schnaider T et al. (1995) Autophosphorylation of grp94 (endoplasmin). J Biol Chem 270(11):6381–6388Google Scholar
  96. 96.
    Edman JC, Ellis L, Blacher RW et al (1985) Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin. Nature 317(6034):267–270PubMedGoogle Scholar
  97. 97.
    Noiva R (1999) Protein disulfide isomerase: the multifunctional redox chaperone of the endoplasmic reticulum. Sem Cell Dev Biol 10(5):481–493Google Scholar
  98. 98.
    Oliver JD, van der Wal FJ, Bulleid NJ et al (1997) Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Science 275:86–88PubMedGoogle Scholar
  99. 99.
    Molinari M, Helenius A (1999) Glycoproteins form mixed disulphides with oxidoreductases during folding in living cells. Nature 402:90–93PubMedGoogle Scholar
  100. 100.
    Corbett EF, Oikawa K, Francois P et al (1999) Ca2+ regulation of interactions between endoplasmic reticulum chaperones. J Biol Chem 274(10):6203–6211PubMedGoogle Scholar
  101. 101.
    Nakamura K, Zuppini A, Arnaudeau S et al (2001) Functional specialization of calreticulin domains. J Cell Biol 154(5):961–972PubMedGoogle Scholar
  102. 102.
    Mesaeli N, Nakamura K, Zvaritch E et al (1999) Calreticulin is essential for cardiac development. J Cell Biol 144(5):857–868PubMedGoogle Scholar
  103. 103.
    Martin V, Groenendyk J, Steiner SS et al (2006) Identification by mutational analysis of amino acid residues essential in the chaperone function of calreticulin. J Biol Chem 281(4):2338–2346PubMedGoogle Scholar
  104. 104.
    Rutkowski DT, Kaufman RJ (2004) A trip to the ER: coping with stress. Trends Cell Biol 14(1):20–28PubMedGoogle Scholar
  105. 105.
    Gething MJ, Sambrook J (1992) Protein folding in the cell. Nature 355:33–45PubMedGoogle Scholar
  106. 106.
    Prostko CR, Dholakia JN, Brostrom MA et al (1995) Activation of the double-stranded RNA-regulated protein kinase by depletion of endoplasmic reticular calcium stores. J Biol Chem 270(11):6211–6215PubMedGoogle Scholar
  107. 107.
    Brostrom CO, Prostko CR, Kaufman RJ et al (1996) Inhibition of translational initiation by activators of the glucose-regulated stress protein and heat shock protein stress response systems. Role of the interferon-inducible double-stranded RNA-activated eukaryotic initiation factor 2alpha kinase. J Biol Chem 271(40):24995–25002PubMedGoogle Scholar
  108. 108.
    Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum- resident kinase. Nature 397(6716):271–274PubMedGoogle Scholar
  109. 109.
    Jeffery J, Kendall JM, Campbell AK (2000) Apoaequorin monitors degradation of endoplasmic reticulum (ER) proteins initiated by loss of ER Ca(2 +). Biochem Biophys Res Commun 268(3):711–715PubMedGoogle Scholar
  110. 110.
    Ma Y, Hendershot LM (2004) ER chaperone functions during normal and stress conditions. J Chem Neuroanat 28(1–2):51–65PubMedGoogle Scholar
  111. 111.
    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(6):326–332PubMedGoogle Scholar
  112. 112.
    DuRose JB, Scheuner D, Kaufman RJ et al (2009) Phosphorylation of eukaryotic translation initiation factor 2alpha coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress. Mol Cell Biol 29(15):4295–4307PubMedGoogle Scholar
  113. 113.
    Shen J, Chen X, Hendershot L et al (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3(1):99–111PubMedGoogle Scholar
  114. 114.
    Cox JS, Shamu CE, Walter P (1993) Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73:1197–1206PubMedGoogle Scholar
  115. 115.
    Munro S, Pelham HR (1986) An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 46(2):291–300PubMedGoogle Scholar
  116. 116.
    Kassenbrock CK, Kelly RB (1989) Interaction of heavy chain binding protein (BiP/GRP78) with adenine nucleotides. EMBO J 8(5):1461–1467PubMedGoogle Scholar
  117. 117.
    Gaut JR, Hendershot LM (1993) Mutations within the nucleotide binding site of immunoglobulin-binding protein inhibit ATPase activity and interfere with release of immunoglobulin heavy chain. J Biol Chem 268(10):7248–7255Google Scholar
  118. 118.
    Lievremont JP, Rizzuto R, Hendershot L et al (1997) BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. J Biol Chem 272:30873–33089PubMedGoogle Scholar
  119. 119.
    Gething MJ (1999) Role and regulation of the ER chaperone BiP. Sem Cell Dev Biol 10(5):465–472Google Scholar
  120. 120.
    Suzuki CK, Bonifacino JS, Lin AY et al (1991) Regulating the retention of T-cell receptor alpha chain variants within the endoplasmic reticulum: Ca2+-dependent association with BiP. J Cell Biol 114(2):189–205PubMedGoogle Scholar
  121. 121.
    Kozutsumi Y, Segal M, Normington K et al (1988) The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332(6163):462–464PubMedGoogle Scholar
  122. 122.
    Ni M, Zhou H, Wey S et al (2009) Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP. PLoS One 4(8):e6868PubMedGoogle Scholar
  123. 123.
    Yoshida H, Haze K, Yanagi H et al (1998) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 273(50):33741–33749PubMedGoogle Scholar
  124. 124.
    Mori K, Kawahara T, Yoshida H et al (1996) Signalling from endoplasmic reticulum to nucleus: transcription factor with a basic-leucine zipper motif is required for the unfolded protein-response pathway. Genes Cells 1:803–817PubMedGoogle Scholar
  125. 125.
    Hong M, Luo S, Baumeister P et al (2004) Underglycosylation of ATF6 as a novel sensing mechanism for activation of the unfolded protein response. J Biol Chem 279(12):11354–11363PubMedGoogle Scholar
  126. 126.
    Yamamoto K, Sato T, Matsui T et al (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 13(3):365–376PubMedGoogle Scholar
  127. 127.
    Thuerauf DJ, Morrison L, Glembotski CC (2004) Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction. J Biol Chem 279(20):21078–21084PubMedGoogle Scholar
  128. 128.
    Hetz C, Glimcher LH (2009) Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell 35(5):551–561PubMedGoogle Scholar
  129. 129.
    Schroder M, Kaufman RJ (2006) Divergent roles of IRE1alpha and PERK in the unfolded protein response. Curr Mol Med 6(1):5–36PubMedGoogle Scholar
  130. 130.
    Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12:1812–1824PubMedGoogle Scholar
  131. 131.
    Yoshida H, Matsui T, Yamamoto A et al (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107(7):881–891PubMedGoogle Scholar
  132. 132.
    Niwa M, Patil CK, DeRisi J et al (2005) Genome-scale approaches for discovering novel nonconventional splicing substrates of the Ire1 nuclease. Gen Biol 6(1):R3Google Scholar
  133. 133.
    Calfon M, Zeng H, Urano F et al (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415(6867):92–96PubMedGoogle Scholar
  134. 134.
    Uemura A, Oku M, Mori K et al (2009) Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during the mammalian unfolded protein response. J Cell Sci 122(Pt 16):2877–2886PubMedGoogle Scholar
  135. 135.
    Lee KP, Dey M, Neculai D et al (2008) Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 132(1):89–100PubMedGoogle Scholar
  136. 136.
    Yamamoto K, Yoshida H, Kokame K et al (2004) Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem 136(3):343–350PubMedGoogle Scholar
  137. 137.
    Lee K, Tirasophon W, Shen X et al (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16(4):452–466PubMedGoogle Scholar
  138. 138.
    Rotin D and Staub O (2011) Role of the ubiquitin system in regulating ion transport. Pflugers Arch 461:1–21Google Scholar
  139. 139.
    Reimold AM, Etkin A, Clauss I et al (2000) An essential role in liver development for transcription factor XBP-1. Genes Dev 14(2):152–157PubMedGoogle Scholar
  140. 140.
    Chen H, Qi L (2010) SUMO modification regulates transcriptional activity of XBP1. Biochem J 429:95–102Google Scholar
  141. 141.
    Urano F, Wang X, Bertolotti A et al (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287(5453):664–666PubMedGoogle Scholar
  142. 142.
    Yoneda T, Imaizumi K, Oono K et al (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276(17):13935–13940PubMedGoogle Scholar
  143. 143.
    Wanderling S, Simen BB, Ostrovsky O et al (2007) GRP94 is essential for mesoderm induction and muscle development because it regulates insulin-like growth factor secretion. Mol Biol Cell 18(10):3764–3775PubMedGoogle Scholar
  144. 144.
    Yang Y, Liu B, Dai J et al (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26(2):215–226PubMedGoogle Scholar
  145. 145.
    Martinon F, Chen X, Lee AH et al. (2010) TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol 11(5):411–418Google Scholar
  146. 146.
    Liu CY, Schroder M, Kaufman RJ (2000) Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum. J Biol Chem 275(32):24881–24885PubMedGoogle Scholar
  147. 147.
    Harding HP, Novoa I, Zhang Y et al (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6(5):1099–1108PubMedGoogle Scholar
  148. 148.
    Scheuner D, Song B, McEwen E et al (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 7(6):1165–1176PubMedGoogle Scholar
  149. 149.
    Toth A, Nickson P, Mandl A et al (2007) Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. Cardiovasc Hematol Disord Drug Targets 7(3):205–218PubMedGoogle Scholar
  150. 150.
    Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11(4):381–389PubMedGoogle Scholar
  151. 151.
    Oyadomari S, Takeda K, Takiguchi M et al (2001) Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci USA 98(19):10845–10850PubMedGoogle Scholar
  152. 152.
    Harding HP, Zeng H, Zhang Y et al (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk −/− mice reveals a role for translational control in secretory cell survival. Mol Cell 7(6):1153–1163PubMedGoogle Scholar
  153. 153.
    Biamonti G, Caceres JF (2009) Cellular stress and RNA splicing. Trends Biochem Sci 34(3):146–153PubMedGoogle Scholar
  154. 154.
    Xie J, Lee JA, Kress TL et al (2003) Protein kinase A phosphorylation modulates transport of the polypyrimidine tract-binding protein. Proc Natl Acad Sci USA 100(15):8776–8781PubMedGoogle Scholar
  155. 155.
    Daoud R, Mies G, Smialowska A et al (2002) Ischemia induces a translocation of the splicing factor tra2-beta 1 and changes alternative splicing patterns in the brain. J Neurosci 22(14):5889–5899PubMedGoogle Scholar
  156. 156.
    Allemand E, Guil S, Myers M et al (2005) Regulation of heterogenous nuclear ribonucleoprotein A1 transport by phosphorylation in cells stressed by osmotic shock. Proc Natl Acad Sci USA 102(10):3605–3610PubMedGoogle Scholar
  157. 157.
    van Oordt W, Diaz-Meco MT, Lozano J et al (2000) The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J Cell Biol 149(2):307–316Google Scholar
  158. 158.
    Lin JC, Hsu M, Tarn WY (2007) Cell stress modulates the function of splicing regulatory protein RBM4 in translation control. Proc Natl Acad Sci USA 104(7):2235–2240PubMedGoogle Scholar
  159. 159.
    Shomron N, Alberstein M, Reznik M et al (2005) Stress alters the subcellular distribution of hSlu7 and thus modulates alternative splicing. J Cell Sci 118(Pt 6):1151–1159PubMedGoogle Scholar
  160. 160.
    Hastings ML, Krainer AR (2001) Functions of SR proteins in the U12-dependent AT-AC pre-mRNA splicing pathway. RNA 7(3):471–482PubMedGoogle Scholar
  161. 161.
    Shin C, Manley JL (2002) The SR protein SRp38 represses splicing in M phase cells. Cell 111(3):407–417PubMedGoogle Scholar
  162. 162.
    Shin C, Feng Y, Manley JL (2004) Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 427(6974):553–558PubMedGoogle Scholar
  163. 163.
    Montaville P, Dai Y, Cheung CY et al (2006) Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22. Biochim Biophys Acta 1763(11):1335–1343PubMedGoogle Scholar
  164. 164.
    Xu D, Friesen JD (2001) Splicing factor slt11p and its involvement in formation of U2/U6 helix II in activation of the yeast spliceosome. Mol Cell Biol 21(4):1011–1023PubMedGoogle Scholar
  165. 165.
    Janowicz A, Michalak M, Krebs J (2010) Stress induced subcellular distribution of ALG-2, RMB22 and hSLU7. Biochem Biophys Acta, doi: 10.1016/j.bbamcr.2010.11.010

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Joachim Krebs
    • 1
    Email author
  • Jody Groenendyk
    • 2
  • Marek Michalak
    • 2
  1. 1.NMR-based Structural BiologyMax Planck Institute for Biophysical ChemistryGoettingenGermany
  2. 2.Department of Biochemistry, School of Molecular and Systems MedicineUniversity of AlbertaEdmontonCanada

Personalised recommendations