Review
ER and aging—Protein folding and the ER stress response
Nirinjini Naidoo
*
Center for Sleep and Respiratory Neurobiology, University of Pennsylvania School of Medicine, 2100 Translational Research Building, 125 South 31st Street,
Philadelphia, PA 19104, United States
1. Introduction
The endoplasmic reticulum (ER) is a sub-cellular organelle
comprised of a reticular membranous network that extends
throughout the cytoplasm and that can be contiguous with the
nuclear envelope. It is the site where all secretory and integral
membrane proteins are folded and post-translationally modified in
ATP dependent chaperone mediated processes. The ER is also a site
of calcium storage, and steroid, cholesterol and lipid biosynthesis.
Protein folding in the oxidizing environment of the ER is an
energy-requiring process (Braakman et al., 1992; Dorner et al.,
1990). Proteins are correctly folded and assembled in the ER prior
to transit to the cell surface or to intracellular organelles. Hence the
ER contains myriad chaperones, foldases, lectins and carbohydrate
processing enzymes to assist proper protein folding. The environ-
ment within the ER is very complex and highly concentrated and
differs substantially from that of the cytosol. Several co-transla-
tional and post-translational modifications that do not occur in the
cyotsol take place in the ER—these include disulfide bond
formation, glycosylation and glycophosphatidylinositol (GPI)
anchor addition. It is estimated that the protein concentration
within the ER lumen approaches 100 mg/ml, a concentration at
which aggregation is promoted (Stevens and Argon, 1999). In
addition there are large numbers of proteins folding concurrently,
thereby exacerbating the likelihood of co-aggregation. The fact
that protein aggregates do not accumulate is due in part to the
existence of ER ‘‘quality control’’ machinery. ER quality control
suppresses the formation of aggregates by ensuring fidelity of
transcription and translation, by chaperoning nascent or unfolded
proteins, and by selectively degrading improperly folded poly-
peptides before they can aggregate (Ellgaard and Helenius, 2003).
Perturbations that alter ER homeostasis consequently disrupt
protein folding and lead to the accumulation of unfolded proteins
and protein aggregates that can be injurious to the cell. ER stress
can be provoked by a variety of physiological conditions, including
perturbations in calcium homeostasis, glucose/energy deprivation,
redox changes, ischemia, hyperhomocystinemia, viral infections
and mutations that impair client protein folding (Kaufman, 2002;
Ron, 2002). As a consequence, the cell has evolved an adaptive co-
ordinated response to limit accumulation of unfolded proteins in
the ER. This signaling pathway is termed the ER stress response or
the unfolded protein response (UPR) [for more detailed reviews see
(Harding et al., 2002; Schroder and Kaufman, 2005a; Zhang and
Kaufman, 2006). This review will cover protein folding and quality
control within the ER, the key components of the ER stress
response, the alterations that occur with age and the consequences
of unresolved ER stress. Several recent studies that examined the
effect of age on the ER stress response system will also be reviewed.
2. Protein folding and quality control
The ER is a membrane bound compartment and the ER lumen is
topologically equivalent to the extracellular space. It is a highly
oxidizing environment that is suitable for protein folding and
Ageing Research Reviews 8 (2009) 150–159
ARTICLE INFO
Article history:
Received 26 January 2009
Received in revised form 19 February 2009
Accepted 4 March 2009
Keywords:
Protein folding
Quality control
Aging
Endoplasmic reticulum stress response
Unfolded protein response
ABSTRACT
The endoplasmic reticulum (ER) is a multifunctional organelle which co-ordinates protein folding, lipid
biosynthesis, calcium storage and release. Perturbations that disrupt ER homeostasis lead to the
misfolding of proteins, ER stress and up-regulation of a signaling pathway called the ER stress response
or the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones,
degradation of misfolded proteins and attenuation of protein translation. Age-related declines and
activity in key molecular chaperones and folding enzymes compromise proper protein folding and the
adaptive response of the UPR. This review will highlight age-related changes in the protein folding
machinery and in the UPR.
ß 2009 Elsevier Ireland Ltd. All rights reserved.
* Tel.: +1 215 746 4811; fax: +1 215 746 4814.
E-mail address: naidoo@mail.med.upenn.edu.
Contents lists available at ScienceDirect
Ageing Research Reviews
journal homepage: www.elsevier.com/locate/arr
1568-1637/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.arr.2009.03.001