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].