The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-κB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection

Abstract

Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds but also by cytokines, toll-like receptor ligands, nucleic acids, lipids, bacteria and viruses. Despite representing unique signaling cascades, new data indicate that the UPR and NF-κB pathways converge within the nucleus through ten major transcription factors (TFs), namely activating transcription factor (ATF)4, ATF3, CCAAT/enhancer-binding protein (CEBP) homologous protein (CHOP), X-box-binding protein (XBP)1, ATF6α and the five NF-κB subunits. The combinatorial occupancy of numerous genomic regions (enhancers and promoters) coordinates the transcriptional activation or repression of hundreds of genes that collectively determine the balance between metabolic and inflammatory phenotypes and the extent of apoptosis and autophagy or repair of cell damage and survival. Here, we also discuss results from genetic experiments and chemical activators of endoplasmic reticulum (ER) stress that suggest a link to the cytosolic inhibitor of NF-κB (IκB)α degradation pathway. These data show that the UPR affects this major control point of NF-κB activation through several mechanisms. Taken together, available evidence indicates that the UPR and NF-κB interact at multiple levels. This crosstalk provides ample opportunities to fine-tune cellular stress responses and could also be exploited therapeutically in the future.

Resveratrol alleviates nuclear factor‐κB‐mediated neuroinflammation in vasculitic peripheral neuropathy induced by ischaemia–reperfusion via suppressing endoplasmic reticulum stress

“…UPR signalling cascades act through the three main ER stress sensor proteins, PERK, IRE1 and ATF6 . It has been known that NF‐κB is critically involved in the inflammatory response within the complex signalling pathways during UPR . Phosphorylation of PERK and IRE1 by ER stress has been linked to downstream NF‐κB activation and subsequent pro‐inflammatory gene transcription .…”

“…35,36 It has been known that NF-κB is critically involved in the inflammatory response within the complex signalling pathways during UPR. 37,38 Phosphorylation of PERK and IRE1 by ER stress has been linked to downstream NF-κB activation and subsequent pro-inflammatory gene transcription. 39 Data from the time-course study revealed that the expression of p-PERK and p-IRE1 was also enhanced during the development of VPN, and was basically correlated to the expression of NF-κB.…”

Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis

“…Our previous study revealed that the application of the NF-κB inhibitor BAY 11-7082 enhanced epithelial apoptosis in experimental colitis 20 , suggesting a role for activated NF-κB in inhibiting apoptosis. Moreover, growing evidence has indicated that NF-κB is involved in the regulation of ER stress signaling and ferroptosis process 21,22 . However, the definite protective mechanisms of NF-κB via the regulation of ER stress-mediated ferroptosis in UC are not completely understood.…”

Effect of Huoxue Jiedu Jiangtang Formulation on Endoplasmic Reticulum Stress in Diabetic Atherosclerosis

“…Therefore, endoplasmic reticulum stress-coupled inflammation plays an important role in the occurrence and development of diabetic atherosclerosis. It has been found that insulin resistance can make macrophages more sensitive to endoplasmic reticulum stress-mediated apoptosis, induce inflammation, macrophage and smooth muscle cell apoptosis, and promote atherosclerosis occurrence and development [16][17]. Antioxidant enzyme system is an important barrier for the body's antioxidant injury, which mainly includes GSH-Px, SOD.…”