Joslin Diabetes Center, Harvard Stem Cell Institute, and Harvard Medical School Department of Genetics, Boston, Massachusetts, United States of America.
PLoS Genet. 2013;9(9):e1003701. doi: 10.1371/journal.pgen.1003701. Epub 2013 Sep 12.
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.
未折叠蛋白反应 (UPR) 维持内质网 (ER) 的内稳态并抵御 ER 应激，后者是各种人类疾病的潜在因素。在 UPR 期间，许多基因被激活，这些基因维持和保护 ER。这些反应已知涉及经典的 UPR 转录因子 XBP1、ATF4 和 ATF6。在这里，我们在秀丽隐杆线虫中表明，保守的应激防御因子 SKN-1/Nrf 在转录 UPR 中发挥核心和必需作用。虽然 SKN-1/Nrf 在保护氧化应激和外源性应激方面具有既定的功能，但我们发现它也动员了与 ER 应激重叠但不同的反应。SKN-1/Nrf 受 UPR 调节，直接控制 UPR 信号和转录因子基因，与 XBP-1 和 ATF-6 结合共同的下游靶标，并存在于 ER 中。SKN-1/Nrf 对于 ER 应激的抵抗也是必需的，包括还原应激。值得注意的是，SKN-1/Nrf 介导的氧化应激反应依赖于 ER 信号。我们得出的结论是，SKN-1/Nrf 在 UPR 中发挥关键作用，但协调了由 ER 信号授权的独特氧化应激反应。通过 SKN-1/Nrf 进行的调节整合可能协调 ER 和细胞质的内稳态。
