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has been reported to decrease with age (432). They suggest that decreased ER
chaperone activity and increased folding stress is one of the underlying mecha-
nisms of aging.
Disulfide bond formation is an essential component of the protein folding
process, and disulfide bonds are required for structural stability, enzymatic
function, and regulation of protein activity (435). The catalytic events involv-
ing the oxidation, reduction, and isomerization of disulfide bonds take place
in the ER. During protein oxidation, PDI introduces native disulfide bonds
into substrate proteins and is reoxidized by the Ero proteins (Ero1p in yeast,
Ero1
in humans) (436). In humans, PDI also contributes to
collagen biosynthesis as a component of the prolyl-4-hydroxylase complex
(437) and can act as a component of the ER degradation machinery, par-
ticularly with respect to the unfolding and retrotranslocation of toxins
(438, 439).
Gadd153, also known as CHOP, is a leucine zipper transcription factor that
is present at low levels under normal conditions but is robustly expressed
in response to oxidative stress (440, 441). Gadd153 was originally identified
based on its induction following treatment of cells with growth-arresting and
DNA-damaging agents, though induced expression of the gene has also been
strongly tied to perturbation of homeostasis in the ER.
As mentioned, proteins destined for transport to the cell membrane or to
the cell exterior are synthesized in the ER and then are extensively modified
by glycosylation and the addition of disulfide bonds. It is in the lumen of the
ER, which provides a unique environment for protein folding, that proteins
assume their mature, tertiary conformation. Disruption of homeostasis in the
ER, which can occur, for example, as a result of nutrient deprivation or altera-
tion of the organelle's calcium-rich oxidizing environment, can have devastat-
ing effects on the cell. Protein misfolding compromises cell function because
essential polypeptides never exit the ER and are thus unable to perform their
normal roles (442, 443). Additionally, accumulation of misfolded proteins
in the ER triggers a unique signaling cascade referred to as the UPR. In the
mammalian UPR, a signal is transduced from the stressed ER to the nucleus,
where transcription of a number of genes, including Gadd153 and genes
encoding ER resident proteins such as the glucose-regulated proteins (Grp
genes), is activated (444, 445). The Grps function as chaperones that guide
proteins through the folding process, and their upregulation in response to
ER stress increases the cell's capacity to cope with the accumulation of imma-
ture, misfolded proteins in the ER. Indeed, if Grp78 induction is prevented,
cell survival diminishes greatly following treatment with agents that stress
the ER (446, 447). Following induction of the UPR, the kinetics of Gadd153
induction parallel exactly those seen for Grp78 (441). However, the effect
of upregulating Gadd153 in response to protein misfolding is much less intui-
tive than the effect of upregulating expression of ER chaperones, and few
studies have expressly addressed what function Gadd153 has in the ER stress
response.
α
and Ero1
β
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