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as ER-associated degradation (ERAD).
84
For proteins
that cannot be retrotranslocated (e.g., because they have
aggregated or assemble into multimers), autophagic
pathways are activated. Portions of ER engorged with
misfolded protein are budded off and become incor-
porated within a double-membrane structure known
as an autophagosome that subsequently fuses with a
lysosome in which the contents are degraded.
83,85,86
Prolonged ER-stress-related UPR can, however, have
detrimental effects on cell function and, in the longer
term, may induce apoptosis.
Chessler and Byers
16
first reported that BiP was
found to specifically bind to the pro-α1(I) chains from
three cell strains in which pro-α1(I) C-propeptide muta-
tions interfered with chain association and interchain
disulfide bonding [p.( Asp1277His), p.(Leu1388Arg) and
p.(Glu1337_Tyr1338del)]. Furthermore, they reported
that BiP levels in the patients' fibroblasts expressing
these mutations were elevated, classic evidence of what
we would nowadays consider to be UPR.
Lamandé et al.
17
and Fitzgerald et al.
87
also showed
that pro-α1(I) C-propeptide mutations, which impair
procollagen trimer assembly, result in increased BiP
expression, but they also provided evidence for ret-
rotranslocation of the misfolded pro-α chains into the
cytosol and degradation via the proteosomal ERAD
pathway. Further evidence that increased ER-stress
and a UPR are associated with alterations in the pro-
collagen type I C-propeptide domain came from a
murine OI model, Aga2. In cultured calvarial osteo-
blasts of these mice, harboring an N-ethyl-N-nitrosurea
(ENU)-induced frameshift mutation that introduces an
extension of 90 amino acids to the C-propeptide of the
pro-α1(I) chain, clear indication of elevated ER stress
and an UPR signature, with increased levels of BiP and
Serpin H1 and increased expression of CHOP, together
with increased rates of caspase-3 dependent apoptosis,
have been described.
88
Intriguingly, collagen type I chains harboring muta-
tions in the triple helical domain do not bind BiP, and
BiP levels in these fibroblasts are not elevated.
16
The lack
of a classical UPR (for example, elevated BiP) in bone
from an OI mouse model resulting from a collagenous
domain mutation (BrtlIV carrying a Gly349Cys substi-
tution in the
Col1a1
gene) has been confirmed by pro-
teomic analysis, although CHOP has been found to be
elevated.
89
The stress pathways triggered by misfolding
collagenous domain mutations remains to be defined.81
81
There is no evidence that ERAD degrades molecules
containing a triple-helical glycine substitution. Although
collagens containing helix mutations have unstable,
poorly formed triple helices, they do associate at their
C-termini and form trimers, and this is likely to pre-
clude them from retrotranslocation and ERAD.
81
More
recently, autophagy routes for protein degradation have
been described for mutant forms of type I collagen that
aggregate within the ER.
86
CONCLUSION
In conclusion, mutations in the
COL1A1
and
COL1A2
genes, affecting the type I procollagen C-propeptide
domain, are a rare cause of autosomal dominant OI,
accounting for only 4% of all reported
COL1A1/A2
muta-
tions. They, however, are of particular importance in view
of the role of the C-propeptides in directing assembly of
the procollagen molecules. Several pro-α1(I) C-propeptide
mutations that impair trimer assembly have been shown
to increase ER stress and induce a UPR. These misfolded
proteins are removed by the proteosomal ER-associated
degradation pathway. The UPR is initially a cytoprotec-
tive response, but, if unresolved, can eventually have
deleterious effects. Besides the pathogenic effect of these
mutations exerted through synthesis of a defective ECM,
either because of a deficiency of wild-type collagen, or
because of the production of a mutant protein, there is
evidence that the cellular consequences of this increased
ER stress may contribute to the pathogenesis. This offers
novel opportunities for therapeutic interventions for
these disorders, as strategies addressing correction of pro-
tein folding, for instance by small chemical chaperones,
may be beneficial.43,90
43,90
References
