Editors' ChoiceCell Biology

Not All Oxidative Stresses Are the Same

Science Signaling  04 Oct 2011:
Vol. 4, Issue 193, pp. ec280
DOI: 10.1126/scisignal.4193ec280

In Saccharomyces cerevisiae, the transcription factor Yap1 is activated by oxidative stress, allowing the cells to mount an adaptive transcriptional response. However, Yap1 is differentially affected by oxidative stress triggered by the thiol-reactive chemical diamide and by H2O2. Diamide modifies cysteines in the C-terminal domain of Yap1, reducing its nuclear export, whereas H2O2 triggers the formation of a complex between glutathione peroxidase (Gpx3), Yap1, and the Yap1-binding protein Ybp1. Gulshan et al. found that yeast overexpressing Ypb1 exhibited increased resistance to H2O2 but were compromised in their growth in the presence of diamide. H2O2 stimulated the enhanced transcription of a Yap1 reporter gene (TRX2-LacZ), whereas induction of this reporter in response to diamide was compromised in cells overexpressing Ypb1. Overexpression of Ypb1 enhanced the formation of the oxidized species of Yap1 in response to H2O2 (based on differential mobility in SDS-PAGE) and blocked the nuclear translocation of Yap1 in response to diamide (based on imaging analysis of fluorescently tagged Yap1). Experiments with purified proteins demonstrated that Yap1 and Ybp1 exhibited a direct interaction and that this complex could be dissociated by the addition of Gpx3 from bacterial lysates treated with H2O2, but not diamide. Coimmunoprecipitation experiments with tagged proteins indicated that Ybp1 was limiting in wild-type cells, because increasing the amount of Ybp1 increased the amount of coimmunoprecipitated Yap1, which is consistent with genetic experiments showing that overexpression of Yap1 did not produce increased resistance to H2O2. A similar system appears to function in the pathogenic yeast Candida glabrata, because overexpression of CgYbp1 also increased H2O2 tolerance and compromised growth in the presence of diamide. Thus, the authors propose that Yap1 exists in two pools, the balance of which depends on the abundance of Ybp1. The “free” pool of Yap1 mediates the response to oxidative stress caused by diamide, whereas the Ybp1-bound pool responds to H2O2-mediated stress.

K. Gulshan, S. S. Lee, W. S. Moye-Rowley, Differential oxidant tolerance determined by the key transcription factor Yap1 is controlled by levels of the Yap1-binding protein,Ybp1. J. Biol. Chem. 286, 34071–34081 (2011). [Abstract] [Full Text]

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