Perspective SKN-1/Nrf, A New Unfolded Protein Response Factor?

Cell function requires simultaneous regulation of numerous processes, often under variable conditions. Several induc-ible pathways have been defined as being responsible for maintaining homeostasis under the threat of a particular stress such as heat, oxidizing conditions, exposure to pathogens, or loss of proteostasis. The challenge now is to understand how and why these pathways interact in basal, stress, and pathological states. The Caenor-habditis elegans inducible transcription fac-tor SKN-1, a homolog of mammalian Nrf proteins, has been defined as the tran-scription factor that responds to oxidative stress. In this issue of PLOS Genetics, Glover-Cutter et al. [1] challenge this paradigm by showing that SKN-1 directly regulates the genes of core regulators and effectors of the endoplasmic reticulum (ER) unfolded protein response (UPR) and that the UPR plays a role in activation of the antioxidant/detoxification response. ER homeostasis requires coordination of protein translation, folding, and cova-lent modification; availability of energy and substrates; and maintenance of a redox environment that is suitable for disulfide bond formation. Disruption of ER homeostasis can cause accumulation of misfolded proteins in the ER lumen, referred to as ‘‘ER stress,’ ’ which can impair cell function and eventually trigger cell death [2–4]. The UPR is a eukaryotic signaling program that responds to ER stress by inhibiting protein translation, inducing protein folding chaperones, and directing the degradation of misfolded proteins [2–4] (Figure 1). Redox homeo-stasis in animal cells is controlled in part by a family of transcription factors repre-sented by SKN-1 in C. elegans and Nrf1, Nrf2, and Nrf3 in mammals (Figure 1). SKN-1 and Nrf2 have well-established roles in promoting redox homeostasis and small molecule detoxification, and SKN-1 has been shown to promote longevity [5– 8]. Glover-Cutter et al. [1] conducted an extensive series of genetic and molecular experiments to investigate regulatory in-teractions between SKN-1 and the UPR; many of their findings are summarized i