SUMMARY
Quality control of the endoplasmic reticulum plays a critical role in protein folding, modification and
modification of a secretory pathway. As endoplasmic reticulum chaperones, calreticulin and calnexin
have similar substrate specificity and share several common features. Yet, surprisingly, mice bearing a
disruption in the calreticulin gene die from a lesion in cardiac development and develop significant
metabolic problems whereas calnexin-deficient mice are born alive with, yet not understood, neurological
problems. Studies with calreticulin and calnexin gene knockout mice and calreticulin- and calnexindeficient
cell lines indicate that calnexin is unable to compensate for the loss of calreticulin and
conversely, calreticulin cannot compensate for the loss of calnexin. Calreticulin or calnexin deficiency or
reduction in the level of ERp57 protein (ERp57 heterozygote mice) leads to development of metabolic
disorders as documented by sever changes serum lipids and carbohydrates composition in these animals.
These observations indicate that calreticulin, calnexin and ERp57, in addition of being involved in
maturation of glycoproteins in the endoplasmic reticulum, perform other distinct functions including
affecting energy metabolism.
KEY WORDS
endoplasmic reticulum; calreticulin; calnexin; chaperones; lipid metabolism
REFERENCES
Arnaudeau S, Frieden M, Nakamura K et al.:
Calreticulin differentially modulates calcium
uptake and release in the endoplasmic
reticulum and mitochondria: J Biol Chem
277:46696-46705, 2002.
Baumann O, Walz B: Endoplasmic reticulum of
animal cells and its organization into structural
and functional domains. Int Rev Cytol
205:149-214, 2001.
Bergeron JJM, Brenner MB, Thomas DY,
Williams DB: Calnexin: a membrane-bound chaperone of the endoplasmic reticulum.
Trends Biochem Sci 19:124-128, 1994.
Burns K, Michalak M: Interactions of calreticulin
with proteins of the endoplasmic and
sarcoplasmic reticulum membranes. FEBS
Lett 318:181-185, 1993.
Camacho P, Lechleiter JD: Calreticulin inhibits
repetitive intracellular Ca2+ waves. Cell
82:765-771, 1995.
Corbett EF, Michalak M: Calcium, a signaling
molecule in the endoplasmic reticulum? Trends
Biochem Sci 25:307-311, 2000.
Corbett EF, Michalak KM, Oikawa K et al.: The
conformation of calreticulin is influenced by
the endoplasmic reticulum lumenal
environment. J Biol Chem 275:27177-27185, 2000.
D'Alessio C, Fernandez F, Trombetta ES,
Parodi AJ: Genetic evidence for the
heterodimeric structure of glucosidase II. The
effect of disrupting the subunit-encoding genes
on glycoprotein folding. J Biol Chem
274:25899-25905, 1999.
Dedhar S: Novel functions for calreticulin:
interaction with integrins and modulation of
gene expression? Trends Biochem Sci
19:269-271, 1994.
Denzel A, Molinari M, Trigueros C, Martin JE,
Velmurgan S, Brown S, Stamp G, Owen
MJ: Early postnatal death and motor disorders
in mice congenitally deficient in calnexin
expression. Mol Cell Biol 22:7398-7404, 2002.
Ellgaard L, Molinari M, Helenius A: Setting the
standards: quality control in the secretory
pathway. Science 286:1882-1888, 1999.
Fadel MP, Dziak E, Lo CM et al.: Calreticulin
affects focal contact-dependent but not close
contact-dependent cell-substratum adhesion. J
Biol Chem 274:15085-15094, 1999.
Fadel MP, Szewczenko-Pawlikowski M,
Leclerc P et al.: Calreticulin affects beta-catenin
associated pathways: J Biol Chem
276:27083-27089, 2001.
Gething MJ: Role and regulation of the ER
chaperone BiP. Sem Cell Dev Biol 10:465-472, 1999.
Guo L, Nakamura K, Lynch J et al.: Cardiacspecific
expression of calcineurin reverses
embryonic lethality in calreticulin-deficient
mouse. J Biol Chem 277:50776-50779, 2002.
High S, Lecomte FJ, Russell SJ et al.:
Glycoprotein folding in the endoplasmic
reticulum: a tale of three chaperones? FEBS
Lett 476:38-41, 2000.
Holaska JM, Black BE, Love DC et al.:
Calreticulin is a receptor for nuclear export.
J Cell Biol 152:127-140, 2001.
Jakob CA, Chevet E, Thomas DY, Bergeron
JJ: Lectins of the ER quality control
machinery. Cell Differ 33:1-17, 2001.
Kapoor M, Srinivas H, Kandiah E et al.:
Interactions of substrate with calreticulin, an
endoplasmic reticulum chaperone. J Biol
Chem 278:6194-6200, 2003.
Knee R, Ahsan I, Mesaeli N et al.: Compromised
calnexin function in calreticulin deficient cells.
Biochem Biophys Res Commun 304:661-666, 2003.
Li J, Puceat M, Perez-Terzic C et al.: Calreticulin
reveals a critical Ca2+ checkpoint in cardiac
myofibrillogenesis. J Cell Biol 158:103-113, 2002.
Meldolesi J, Pozzan T: The endoplasmic
reticulum Ca2+ store: a view from the lumen.
Trends Biochem Sci 23:10-14, 1998.
Mesaeli N, Phillipson C: Impaired p53 expression,
function, and nuclear localization in
calreticulin-deficient cells. Mol Biol Cell 15:1862-1870, 2004.
Mesaeli N, Nakamura K, Zvaritch E et al.:
Calreticulin is essential for cardiac
development. J Cell Biol 144:857-868, 1999.
Michalak M, Corbett EF, Mesaeli N et al.:
Calreticulin: one protein, one gene, many
functions. Biochem J 344:281-292, 1999.
Michalak M, Parker JMR, Opas M: Ca2+
signaling and calcium binding chaperones of
the endoplasmic reticulum. Cell Calcium
32:269-278, 2002.
Molinari M, Helenius A: Chaperone selection
during glycoprotein translocation into the
endoplasmic reticulum. Science 288:331-333, 2000.
Molinari M, Eriksson KK, Calanca V et al.:
Contrasting functions of calreticulin and
calnexin in glycoprotein folding and ER
quality control. Mol Cell 13:125-135, 2004.
Muller-Taubenberger A, Lupas AN, Li H et al.:
Calreticulin and calnexin in the endoplasmic
reticulum are important for phagocytosis.
EMBO J 20:6772-6782, 2001.
Nakamura K, Bossy-Wetzel E, Burns K et al.:
Changes in endoplasmic reticulum luminal
environment affect cell sensitivity to apoptosis.
J Cell Biol 150:731-740, 2000.
Nakamura K, Zuppini A, Arnaudeau S et al.:
Functional specialization of calreticulin
domains. J Cell Biol 154:961-972, 2001.
Nauseef WM, McCormick SJ, Clark RA:
Calreticulin functions as a molecular
chaperone in the biosynthesis of
myeloperoxidase. J Biol Chem 270:4741-4747, 1995.
Nicchitta CV: Biochemical, cell biological and
immunological issues surrounding the
endoplasmic reticulum chaperone GRP94/gp96. Curr Opin Immunol 10:103-109, 1998.
Opas M, Szewczenko-Pawlikowski M, Jass GK
et al.: Calreticulin modulates cell adhesiveness
via regulation of vinculin expression. J Cell
Biol 135:1913-1923, 1996.
Parlati F, Dignard D, Bergeron JJM, Thomas
DY: The calnexin homologue cnx1+ in
Schizosaccharomyces pombe, is an essential
gene which can be complemented by its
soluble ER domain. EMBO J 14:3064-3072, 1995a.
Parlati F, Dominguez M, Bergeron JJM, Thomas
DY: Saccharomyces cerevisiae CNE1
encodes an endoplasmic reticulum (ER)
membrane protein with sequence similarity to
calnexin and calreticulin and functions as a
constituent of the ER quality control apparatus.
J Biol Chem 270:244-253, 1995b.
Roderick HL, Lechleiter JD, Camacho P:
Cytosolic phosphorylation of calnexin controls
intracellular Ca2+ oscillations via an interaction
with SERCA2b. J Cell Biol 149:1235-1248, 2000.
Rusnak F, Mertz P: Calcineurin: form and
function. Physiol Rev 80:1483-1521, 2000.
Russell SJ, Ruddock LW, Salo KEH et al.:
The primary substrate binding site in the b'
domain of ERp57 is adapted for endoplasmic
reticulum lectin association. J Biol Chem
279:18861-18869, 2004.
Saito Y, Ihara Y, Leach MR et al.: Calreticulin
functions in vitro as a molecular chaperone for
both glycosylated and non-glycosylated
proteins. EMBO J 18:6718-6729, 1999.
Scott JE, Dawson JR: MHC class I expression
and transport in a calnexin-deficient cell line. J
Immunol 155:143-148, 1995.
Silvennoinen L, Myllyharju J, Ruoppolo M et al.:
Identification and characterization of structural
domains of human ERp57 - association with
calreticulin requires several domains.
J Biol Chem 279:13607-1361, 2004.
Trombetta ES: The contribution of N-glycans and
their processing in the endoplasmic reticulum
to glycoprotein biosynthesis. Glycobiology
13:77-91, 2003.
Trombetta ES, Parodi AJ: Quality control and
protein folding in the secretory pathway. Annu
Rev Cell Dev Biol 19:649-676, 2003.
Wada I, Rindress D, Cameron PH et al.:
SSR alpha and associated calnexin are major
calcium binding proteins of the endoplasmic
reticulum membrane. J Biol Chem
266:19599-19610, 1991.
Xu K, Tavernarakis N, Driscoll M: Necrotic cell
death in C. elegans requires the function of
calreticulin and regulators of Ca2+ release from
the endoplasmic reticulum. Neuron 31:957-971, 2001.
Zapun A, Darby NJ, Tessier DC et al.: Enhanced
catalysis of ribonuclease B folding by the
interaction of calnexin or calreticulin with
ERp57. J Biol Chem 273:6009-6012, 1998.
Zapun A, Jakob CA, Thomas DY, Bergeron
JJM: Protein folding in a specialized
compartment: the endoplasmic reticulum.
Structure Fold Des 7:R173-R182, 1999.
Zuppini A, Groenendyk J, Cormack LA et al.:
Calnexin deficiency and endoplasmic
reticulum stress-induced apoptosis:
Biochemistry 41:2850-2858, 2002.
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