Biomedical Engineering Reference
In-Depth Information
The ER is a network of tubules, vesicles and sacs that are interconnected. It is
continuous with the outer membrane of the nucleus and is subdivided into the rough
ER (RER) and smooth ER (SER) based on the association of ribosomes with the
ER membrane. The ER is more voluminous in cells involved in drug metabolism
or secretion of proteins or lipid. The ER is involved in (1) secretory proteins, mem-
brane proteins and lipid synthesis and exchange, (2) protein modification, folding
and quality control, (3) calcium sequestration and (4) drug detoxification (Dancourt
and Barlowe 2010 ; Hu et al. 2010 ; Michalak and Opas 2009 ; Neve and Ingelman-
Sundberg 2010 ). Protein synthesis begins on the ribosome complex, which may be
transported to the ER surface via a signal-sequence-recognition mechanism, after
which translation resumes. The ER is also responsible for glycosylation, the
enzyme-mediated placement of an oligosaccharide tag that marks the state of pro-
tein folding. Correct protein folding is mediated by several ER-resident, chaperone
proteins, such as Protein Disulfide Isomerase (PDI), and Binding immunoglobulin
Protein (BiP), which bind the glucose moiety on improperly folded proteins. The
chaperone proteins bind misfolded or unassembled proteins, preventing aggrega-
tion and directing the protein for degradation or proper folding. Proteins, such as
lysosomal enzymes, are sorted and sequestered from the other luminal contents due
to their potential degradative or aggregative effects. Only properly folded, nascent
polypeptides are released from the chaperones and transported from the rough ER
to the Golgi. Shuttling between the ER and Golgi is mediated by signal peptides
and oligosaccharide chains. Coat proteins and KDEL (Lys-Asp-Glu-Leu)-receptors
(KDEL-R) facilitate directed transport between organelles (Fig. 4 ). KDEL-R has
different affinity for KDEL in Golgi (slightly acidic pH) and ER (neutral pH). Thus
the receptor goes between the Golgi and ER to retrieve more KDEL-bearing pro-
teins (Capitani and Sallese 2009 ). Several studies exploit this property and use
KDEL-GFP as a fluorescent ER marker (Watson et al. 2005 ).
Other ER functions include lipid elongation and desaturation, calcium seques-
tration, drug detoxification and cell-protective mechanisms. Lipid synthesis is
enzyme-mediated, utilizing fatty acid synthase complexes and desaturases.
Deviations in this process correlate with diabetes, obesity, cardiovascular disease,
and cancer. The ER also contains enzymes for drug detoxification, as seen in the
hepatocyte. Cytochrome p450 enzymes metabolize water insoluble drugs or metab-
olites to facilitate excretion. Another enzyme, protein disulfide isomerase, oxidizes
sulfhydryl groups. The lumen of the ER is thus an oxidizing environment, which
contrasts with the reducing environment of the cytosol. The ER Stress Response is
an important function to adjust the cell's protein content. An accumulation of
unfolded proteins causes the ER to attenuate translation, arrest the cell cycle by the
PERK (proline-rich, extensin-like receptor kinase) receptor, and upregulate the
chaperone proteins to assist in protein folding. If the accumulation is severe or
prolonged, apoptosis is induced.
Several methods have been used to target the ER. Peptides exploit natural traf-
ficking mechanisms to the ER. In particular, bacterial and viral peptides navigate
the intracellular compartments to mediate their toxic effects. Cholera toxin is one
of the peptides known for its ability to traffic to the ER and escape to the cytosol to
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