Abstract
ABSTRACTAdaptation of Saccharomyces cerevisiae cells to arsenic stress is mediated through the activation of arsenic detoxification machinery by the Yap8 transcription factor. Yap8 is targeted by the ubiquitin proteasome system for degradation under physiological conditions, yet it escapes proteolysis in arsenic-injured cells by a mechanism that remains to be elucidated. Here, we show that Ufd2, an E4-Ubiquitin (Ub) ligase, is upregulated by arsenic compounds both at mRNA and protein levels. Under these conditions, Ufd2 interacts with Yap8 mediating its stabilization, thereby controlling expression of ACR3 and capacity of cells to adapt to arsenic injury. We also show that Ufd2 U-box domain, which is associated to the ubiquitination activity of specific ubiquitin ligases, is dispensable for Yap8 stability and has no role in cell tolerance to arsenic stress. Thus, our data disclose a novel Ufd2 role beyond degradation. This finding is further supported by genetic analyses showing that proteins belonging to Ufd2 proteolytic pathways, namely Ubc4, Rad23 and Dsk2, mediate Yap8 degradation.
Highlights
Arsenic (As) is a toxic element widely spread in nature due to natural and anthropogenic sources (Mandal and Suzuki, 2002)
Yap8 levels are tightly controlled by arsenic Arsenic stress responses in S. cerevisiae require the AP-1 like transcription factor Yap8, which drives the expression of genes involved in As detoxification processes (Menezes et al, 2004)
Ufd2 stabilizes Yap8 independent of the ubiquitinproteasome pathway As to determine whether Ufd2 role on Yap8 stabilization is connected to ubiquitin-proteasome pathway (UPP) we investigated the requirement of the UPP components Ubc4, Rad23 and Dsk2 to Yap8 stability under arsenic stress conditions
Summary
Arsenic (As) is a toxic element widely spread in nature due to natural and anthropogenic sources (Mandal and Suzuki, 2002). In the yeast Saccharomyces cerevisiae, protective response to arsenic stress involves multiple cellular mechanisms They include the activation of antioxidant defense machinery, the calciumsignaling pathways, the repression of the high affinity iron uptake system, the adjustment of sulfur metabolism to enhance GSH biosynthesis associated to intra- and extra-cellular chelation of arsenic, the regulation of cell cycle progression as well as Instituto de Tecnologia Quıḿ ica e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, EAN, Oeiras 2781-901, Portugal. They include the activation of antioxidant defense machinery, the calciumsignaling pathways, the repression of the high affinity iron uptake system, the adjustment of sulfur metabolism to enhance GSH biosynthesis associated to intra- and extra-cellular chelation of arsenic, the regulation of cell cycle progression as well as Instituto de Tecnologia Quıḿ ica e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, EAN, Oeiras 2781-901, Portugal. *Present address: iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, Oeiras 2781-901, Portugal and ITQB, Instituto de Tecnologia Quıḿ ica e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, EAN, Oeiras 2780-157, Portugal.
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