Central Role of the Scaffold Protein Tumor Necrosis Factor Receptor-associated Factor 2 in Regulating Endoplasmic Reticulum Stress-induced Apoptosis

Abstract

The endoplasmic reticulum represents the quality control site of the cell for folding and assembly of cargo proteins. A variety of conditions can alter the ability of the endoplasmic reticulum (ER) to properly fold proteins, thus resulting in ER stress. Cells respond to ER stress by activating different signal transduction pathways leading to increased transcription of chaperone genes, decreased protein synthesis, and eventually to apoptosis. In the present paper we analyzed the role that the adaptor protein tumor necrosis factorreceptor associated factor 2 (TRAF2) plays in regulating cellular responses to apoptotic stimuli from the endoplasmic reticulum. Mouse embryonic fibroblasts derived from TRAF2؊/؊ mice were more susceptible to apoptosis induced by ER stress than the wild type counterpart. This increased susceptibility to ER stress-induced apoptosis was because of an increased accumulation of reactive oxygen species following ER stress, and was abolished by the use of antioxidant. In addition, we demonstrated that the NF-B pathway protects cells from ER stress-induced apoptosis, controlling ROS accumulation. Our results underscore the involvement of TRAF2 in regulating ER stress responses and the role of NF-B in protecting cells from ER stress-induced apoptosis.

Tumor cell dormancy induced by p38SAPK and ER-stress signaling: An adaptive advantage for metastatic cells?

“…60 An alternative survival mechanism could be attributed to IRE1-mediated activation of TRAF2, which activates the survival transcription factor NF-κB. 61,62 The fact that MEFs lacking TRAF2 are more susceptible to ER-stress than their WT counterparts, 63 supports this hypothesis. Although p38 signaling may induce apoptosis, these observations suggest that, alternatively, it might also protect and prepare cells to imminent stress.…”

Forkhead Transcription Factors (FoxOs) Promote Apoptosis of Insulin-Resistant Macrophages During Cholesterol-Induced Endoplasmic Reticulum Stress

“…At least a part of the role of FoxOs in promoting apoptosis during endoplasmic reticulum stress involved an attenuation of the increased NF-B response that is characteristic of the UPR and has an antiapoptotic function in this context (43). The mechanism of increased NF-B activity during the UPR is not well understood (12).…”

Engineering of chaperone systems and of the unfolded protein response

“…-/-and p65 -/-cells were more sensitive to ER stress than WT cells (Mauro et al 2006). Activation of NF-jB by IRE1 through IKK (Hu et al 2006) inhibits JNK through suppression of ROS (Pham et al 2004) and induction of GADD45b which interferes with activation of the JNK kinase MKK7 .…”

“…NF-jB induces cIAPs to suppress apoptosis (Wajant and Scheurich 2001). It is more difficult to understand why traf2 -/-cells, in contrast to ask1 -/-cells for example, are more sensitive to ER stress (Mauro et al 2006). Both, TRAF2 and ASK1, are required for activation of p38, but TRAF2, through interaction with IRE1a mediates activation of IKK and NF-jB, which suppresses JNK-induced apoptosis.…”

“…NF-jB protects cells from tumor necrosis factor (TNF)-stimulated ROS accumulation through induction of ferritin heavy chain (Pham et al 2004). MEFs deleted for the p65 subunit of NF-jB accumulate ROS during ER stress (Mauro et al 2006), suggesting that NF-jB has an antioxidant function in the UPR. NRF2 resides within the cytosol of unstressed cells in association with the cytoskeletal anchor protein KEAP1 (Cullinan and Diehl 2006).…”