Oxidation of ER Resident Proteins Upon Oxidative Stress: Effects of Altering Cellular Redox/Antioxidant Status and Implications for Protein Maturation

Abstract

Previous work showed that from all cellular proteins, the endoplasmic reticulum (ER) resident proteins are most sensitive to oxidative stress [hydrogen peroxide (H(2)O(2))], as determined using the oxidation-sensitive, membrane-permeable, acetylTyrFluo probe. Because of the importance of these proteins in proper cellular functioning, we studied (a) whether modifying the cellular redox state/antioxidant status alters the susceptibility of those proteins toward H(2)O(2) oxidative stress and (b) whether H(2)O(2) affects ER function with regard to protein folding. The cellular redox and/or antioxidative capacity was modified in several ways. Lowering the capacity increased H(2)O(2)-induced protein oxidation, and increasing the capacity lowered H(2)O(2)-induced protein oxidation. The effect of H(2)O(2) on ER-related protein maturation was investigated, using the maturation of the low-density lipoprotein receptor as a model. Its maturation was not affected at low concentrations of H(2)O(2) (< or = 400 micro M), which do result in oxidation of ER resident proteins. Maturation was slowed down or reversibly inhibited at higher concentrations of H(2)O(2) (1.5-2.0 mM). These results might be caused by several events, including oxidation of the low-density lipoprotein receptor itself or ER resident proteins resulting in decreased folding (capacity). Alternatively, oxidation of cytosolic proteins involved in ER Golgi transport might attenuate transport and maturation. Clearly, the mechanism(s) responsible for the impairment of maturation need further investigation.

C/EBP Homologous Protein Deficiency Attenuates Myocardial Reperfusion Injury by Inhibiting Myocardial Apoptosis and Inflammation

“…25 Additionally, ROS can directly perturb redox homeostasis within the ER lumen, which specializes in protein folding and disulfide bond formation, 26 and can even cause oxidative damage to ER-resident proteins directly or indirectly through lipid peroxidation. 27,28 All of these features evoke the idea that ROS induce misfolded protein accumulation and the subsequent ER stress response, but such reports are scarce. Here, in a model of myocardial I/R, we have demonstrated for the first time that excess production of ROS, especially superoxide, after reperfusion has a critical role in activating the ER stress response pathways.…”

“…6,23,24 On the other hand, ROS is thought to be a cause of ER stress via several mechanisms, 2,7,8,[25][26][27][28] but whether the ROS overproduction after myocardial I/R triggers the CHOP-related ER stress response remains unclear. Thus, we assessed the potential effects of edaravone, a free radical scavenger clinically available in Japan, 29 on regulation of ER stress after myocardial I/R.…”

Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1

“…These lipid peroxides could have resulted from triglyceride peroxidation under oxidative stress. Endoplasmic reticulum resident proteins are known to be most sensitive to oxidative stress (41)(42)(43), but no data are available yet on the effect of oxidative stress on DGAT1 activity. We have now clearly demonstrated that in PON2-deficient MPMs that were treated with the free radical generator AAPH, the cellular oxidative stress increased, followed by an increment in DGAT1 activity.…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Conversely, ROS accumulation can induce the oxidation of resident ER proteins, including proteins of the polypeptide folding machinery such as PDI and BiP (van der Vlies et al. 2002, 2003), thus leading to an ER stress and creating a vicious cycle (Malhotra and Kaufman 2007). To alleviate the deleterious effects of ROS, the PERK branch of the UPR can activate the transcription of several key antioxidant enzymes via the phosphorylation of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) (Cullinan and Diehl 2006; Flamment et al.…”