Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf

Abstract

The Unfolded Protein Response (UPR) maintains homeostasis in the endoplasmic reticulum (ER) and defends against ER stress, an underlying factor in various human diseases. During the UPR, numerous genes are activated that sustain and protect the ER. These responses are known to involve the canonical UPR transcription factors XBP1, ATF4, and ATF6. Here, we show in C. elegans that the conserved stress defense factor SKN-1/Nrf plays a central and essential role in the transcriptional UPR. While SKN-1/Nrf has a well-established function in protection against oxidative and xenobiotic stress, we find that it also mobilizes an overlapping but distinct response to ER stress. SKN-1/Nrf is regulated by the UPR, directly controls UPR signaling and transcription factor genes, binds to common downstream targets with XBP-1 and ATF-6, and is present at the ER. SKN-1/Nrf is also essential for resistance to ER stress, including reductive stress. Remarkably, SKN-1/Nrf-mediated responses to oxidative stress depend upon signaling from the ER. We conclude that SKN-1/Nrf plays a critical role in the UPR, but orchestrates a distinct oxidative stress response that is licensed by ER signaling. Regulatory integration through SKN-1/Nrf may coordinate ER and cytoplasmic homeostasis.

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

“…Nrf1 and Nrf3 proteins of this family have been reported to be associated with the ER membrane and nuclear envelope which suggest their involvement in ER-related functions [43,44]. A study in Caenorhabditis elegans [45] revealed that SKN-1, the Nrf ortholog, plays a critical role in resistance to oxidative and ER stress. Moreover, it has been reported that the response mobilized by SKN-1/Nrf under UPR is observed to be overlapping but still distinct from that evoked during oxidative stress conditions [45].…”

“…A study in Caenorhabditis elegans [45] revealed that SKN-1, the Nrf ortholog, plays a critical role in resistance to oxidative and ER stress. Moreover, it has been reported that the response mobilized by SKN-1/Nrf under UPR is observed to be overlapping but still distinct from that evoked during oxidative stress conditions [45]. SKN-1/ Nrf is reported to be activated by ER stress, independent of ROS signaling, and it provides resistance against reductive stress as well [45].…”

“…Moreover, it has been reported that the response mobilized by SKN-1/Nrf under UPR is observed to be overlapping but still distinct from that evoked during oxidative stress conditions [45]. SKN-1/ Nrf is reported to be activated by ER stress, independent of ROS signaling, and it provides resistance against reductive stress as well [45]. Furthermore, studies also report that PERK activates nuclear respiratory factor 2 (Nrf2) [17].…”

Interplay between redox and protein homeostasis

“…By analyzing hsp-4 mRNA levels and using an hsp-4::gfp reporter it was confirmed that knockdown of ero-1 leads to UPR ER activation. 54,56,57 These findings indicate that the oxidases and PDIs play a central role in maintaining proteostasis of the ER.…”

Enhanced Oxidative Stress Resistance through Activation of a Zinc Deficiency Transcription Factor inBrachypodium distachyon

“…In plants, exploration of specific basic leucine zipper (bZIP) oxidative stress transcription factors has mostly focused on the TGA bZIP family, which bears some resemblance to the yeast (Saccharomyces cerevisiae) phase II detoxification factor YEAST AP-1-LIKE (Johnson et al, 2001;Després et al, 2003). In the animal kingdom, many stress transcription factors are utilized during oxidative stress to activate protective responses (bZIP transcription factors X-BOX BINDING PROTEIN1, ACTIVATING TRANSCRIPTION FACTOR4 [ATF4], NF-E2-RELATED FACTOR1-3, and ATF6; An and Blackwell, 2003;Harding et al, 2003;Glover-Cutter et al, 2013), with many of these factors playing intersecting roles in related cellular stresses, including protein homeostasis and aging (Henis-Korenblit et al, 2010;Kenyon, 2010;Hetz, 2012).…”