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.
Highlights
The endoplasmic reticulum (ER) is responsible for multiple functions in protein synthesis and processing, lipid metabolism, xeno/endobiotic detoxification, and Ca2+ storage
The ER protects against a toxic buildup of misfolded proteins by activating the unfolded protein response (UPR), which maintains ER homeostasis by slowing protein synthesis and enhancing ER functions such as protein folding and degradation
We report that SKN-1/ Nrf mobilizes an ER stress gene network that is distinct from its oxidative stress response, and includes regulation of other central Unfolded Protein Response (UPR) factors
Summary
The endoplasmic reticulum (ER) is responsible for multiple functions in protein synthesis and processing, lipid metabolism, xeno/endobiotic detoxification, and Ca2+ storage (reviewed in [1,2]). All secretory and membrane-bound proteins are synthesized in the rough ER, a process that is highly regulated so that only properly folded and modified proteins are released to the Golgi [1,2,5,6]. When its protein folding capacity is exceeded (ER stress), the ER protects itself through the Unfolded Protein Response (UPR) (Figure S1A) [2,5,6]. This signaling and transcription program decreases protein translation, expands ER size and folding capacity, and directs misfolded proteins to be degraded in the cytosol. ER stress and the UPR have been implicated in many human diseases, including diabetes, inflammatory disease, neurodegenerative disease, secretory cell malignancies, and other cancers [6,11,12]
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