The conserved role of the phase 2 detoxification system in limiting the damage caused by xenobiotics and reactive oxygen species underlies its importance in stress resistance and longevity. In C. elegans the ortholog of the mammalian bZIP transcription factor Nrf2, SKN-1, activates the expression of phase 2 genes such as
gcs-1, which encodes an enzyme important for glutathione synthesis and arsenite resistance. Several signalling pathways regulate levels of active SKN-1. For example, phosphorylation of SKN-1 by the stress-activated
p38-related PMK-1 MAPK plays a critical role in promoting SKN-1 activity to increase phase 2 gene expression and stress resistance (1). However, the increased
gcs-1 expression and arsenite stress resistance associated with loss of the 2-Cys peroxiredoxin PRDX-2 is only partially dependent on SKN-1, suggesting the existence of other mechanisms for regulating phase 2 detoxification gene expression and arsenite resistance (2). Hence, to identify new regulators of phase II detoxification, we have performed a genome-wide RNAi screen for genes required for the elevated expression of a Pgcs-1::GFP transcriptional reporter in
prdx-2 mutant worms. 39 of the 170 genes identified by this screen were also found to be required for the arsenite-induced expression of Pgcs-1::GFP in wild-type animals. These genes include
tir-1 and
rack-1, which encode signaling proteins that have been suggested to act upstream of the PMK-1 MAPK to promote wound healing and innate immunity (3). However, our data suggests that both RACK-1 and TIR-1 act to increase
gcs-1 expression and arsenite resistance independently from PMK-1. We will present studies addressing the mechanisms by which RACK-1, TIR-1 and other regulators identified in this screen promote phase 2 gene expression in
prdx-2 mutant animals and in response to arsenite. Our improved understanding of these mechanisms provides important insight into how PRDX-2 and phase II detoxification systems contribute to stress resistance and longevity. 1.Inoue, H., Hisamoto, N., An, J. H., Oliveira, R. P., Nishida, E., Blackwell, T. K., and Matsumoto, K. (2005) Genes Dev 19, 2278-2283 2.Olahova, M., Taylor, S. R., Khazaipoul, S., Wang, J., Morgan, B. A., Matsumoto, K., Blackwell, T. K., and Veal, E. A. (2008) Proc Natl Acad Sci U S A 3.Ziegler, K., Kurz, C. L., Cypowyj, S., Couillault, C., Pophillat, M., Pujol, N., and Ewbank, J. J. (2009) Cell Host Microbe 5, 341-352.