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Methionine sulphoxide reductases protect iron–sulphur clusters from oxidative inactivation in yeast

Theodora C. Sideri

School of Biology, Institute of Genetics, University of Nottingham, Nottingham NG7 2RD, UK

Correspondence
Simon V. Avery
Simon.Avery{at}nottingham.ac.uk

Methionine residues and iron–sulphur (FeS) clusters are primary targets of reactive oxygen species in the proteins of micro-organisms. Here, we show that methionine redox modifications help to preserve essential FeS cluster activities in yeast. Mutants defective for the highly conserved methionine sulphoxide reductases (MSRs; which re-reduce oxidized methionines) are sensitive to many pro-oxidants, but here exhibited an unexpected copper resistance. This phenotype was mimicked by methionine sulphoxide supplementation. Microarray analyses highlighted several Cu and Fe homeostasis genes that were upregulated in the mxr double mutant, which lacks both of the yeast MSRs. Of the upregulated genes, the Cu-binding Fe transporter Fet3p proved to be required for the Cu-resistance phenotype. FET3 is known to be regulated by the Aft1 transcription factor, which responds to low mitochondrial FeS-cluster status. Here, constitutive Aft1p expression in the wild-type reproduced the Cu-resistance phenotype, and FeS-cluster functions were found to be defective in the mxr mutant. Genetic perturbation of FeS activity also mimicked FET3-dependent Cu resistance. ⁵⁵Fe-labelling studies showed that FeS clusters are turned over more rapidly in the mxr mutant than the wild-type, consistent with elevated oxidative targeting of the clusters in MSR-deficient cells. The potential underlying molecular mechanisms of this targeting are discussed. Moreover, the results indicate an important new role for cellular MSR enzymes in helping to protect the essential function of FeS clusters in aerobic settings.

Present address: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

Five supplementary figures, showing Cu resistance in the fet4, mxr and mxr/fet4 mutants, that overexpression of FET3 or SOD1 confers Cu resistance, that CUP1 may partially contribute to the Cu resistance of the mxr mutant, Bio2 protein in immunoprecipitates from wild-type and mxr cells, and determination of ⁵⁵Fe incorporation into FeS proteins, and a supplementary table listing genes upregulated at least twofold in msr versus wild-type cells, are available with the online version of this paper.