Xenobiotic Perturbation of ER Stress and the Unfolded Protein Response

Abstract

The proper folding, assembly, and maintenance of cellular proteins is a highly regulated process and is critical for cellular homeostasis. Multiple cellular compartments have adapted their own systems to ensure proper protein folding, and quality control mechanisms are in place to manage stress due to the accumulation of unfolded proteins. When the accumulation of unfolded proteins exceeds the capacity to restore homeostasis, these systems can result in a cell death response. Unfolded protein accumulation in the endoplasmic reticulum (ER) leads to ER stress with activation of the unfolded protein response (UPR) governed by the activating transcription factor 6 (ATF6), inositol requiring enzyme-1 (IRE1), and PKR-like endoplasmic reticulum kinase (PERK) signaling pathways. Many xenobiotics have been shown to influence ER stress and UPR signaling with either pro-survival or pro-death features. The ultimate outcome is dependent on many factors including the mechanism of action of the xenobiotic, concentration of xenobiotic, duration of exposure (acute vs. chronic), cell type affected, nutrient levels, oxidative stress, state of differentiation, and others. Assessing perturbations in activation or inhibition of ER stress and UPR signaling pathways are likely to be informative parameters to measure when analyzing mechanisms of action of xenobiotic-induced toxicity.

Divergent forms of endoplasmic reticulum stress trigger a robust unfolded protein response in honey bees

“…Naturally occurring and synthetic biologically active compounds can impact the UPR through diverse mechanisms (Cribb et al, 2005;Kitamura, 2013;Lafleur et al, 2013). For example, known biological compounds affect N-glycosylation, cellular redox, the secretory pathway, ERAD function, or Ca 2+ homeostasis and exposure to these chemicals leads to unfolded proteins in the ER, stimulating the UPR.…”

“…In other species, the UPR has been shown to influence cellular and organismal outcomes to exposures to the very environmental stressors suspected to play a part in recent honey bee losses, including microbial attack (Wang and Kaufman, 2012), chemical toxicity (Lafleur et al, 2013), nutritional stress (Lee and Ozcan, 2014), and physiological stress (Taylor et al, 2014). A few highly conserved pathways, characterized by unique receptors and signal transduction machinery, are responsible for sensing unfolded proteins in the ER (Fig.…”

Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries

“…Xenobiotics release reactive electrophiles that are possibly connected to nuclear aggregation and endoplasmic reticulum (ER) stress [129] with protein deposits in cells (Figure 4). The damage to DNA occurring in neuronal cells with xenobiotics is with the formation of DNA adducts, DNA strand breakage and altered DNA function [127,130].…”

Disrupted ER‐to‐Golgi trafficking underlies anti‐HIV drugs and alcohol‐induced cellular stress and hepatic injury

“…Xenobiotics, including molecular chaperones (e.g., 4-phenylbutyrate and tauroursodeox-ycholic acid) and UPR enhancers (e.g., salubrinal and valproate) to ensure proper ER homeostasis have been developed and tested in a variety of in vitro and in vivo models. (20) However, these compounds for restoration of ER homeostasis only yield limited protective effects. The incomplete protections through targeting the ER suggest that although ER stress is involved in alcohol and drug-induced hepatotoxicity, there are other drug and alcohol-targeted cellular components that either enhance or are upstream of the ER stress response.…”