Introduction to the UPR pathway
The endoplasmic reticulum (ER) is a vital cellular component and this
dynamic tubular network has an important role in several essential
cellular functions such as protein synthesis, folding, maturation, and
translocation, along with regulating second messenger signaling,
carbohydrate metabolism, maintenance of calcium storage and biogenesis
of cholesterol, steroids, and lipids[1]–[3]. Alteration in
physiological statuses such as oxidative stress, Ca2+imbalance, drastic pH and temperature variations, and pathological
conditions such as ischaemia, reperfusion and bacterial, viral, or
protozoan infections can cause loss of ER homeostasis by disrupting the
protein folding process[2], [4].
Interference with the protein
folding process leads to the accumulation of unfolded and misfolded
proteins in ER lumen subsequently
triggering a cellular condition
known as the “ER stress”[3].
As a response to ER stress, ER induces an adaptive signaling cascade to
restore protein homeostasis in ER and ensure cellular survival. This
signaling cascade is collectively known as the Unfolded Protein Response
(UPR), also known as the ER stress response[2], [4]. These
adaptive signal transduction pathways help to increase the folding
capacity of the proteins in the ER and get rid of the misfolded proteins
accumulated in ER, thus helping the organelle to offload the proteins
that are not properly folded[1], [3], [5]. During this
process, genes that are responsible for the expression of cytokines and
induction of resistance to oxidative stress are upregulated[1]. If
these UPR mechanisms fail to restore the ER homeostasis, the cell will
undergo apoptosis[6]. Traditionally, UPR is triggered by the
accumulation of misfolded or unfolded proteins. But since UPR is
significantly interconnected with inflammation and innate immune
response pathways, pathogenic infections also can trigger the UPR
signaling cascades[2], [7]. Intracellular pathogens can induce
the UPR pathway as a response to a wide variety of cellular
perturbations such as disruptions of the secretory pathways,
accumulation of Reactive oxygen species (ROS), or increase of free fatty
acids and nutrient depletion[8].