Abstract
Methylglyoxal, a toxic metabolite synthesized in vivo during glycolysis, inhibits cell growth. One of the mechanisms protecting eukaryotic cells against its toxicity is the glyoxalase system, composed of glyoxalase I and II (glo1 and glo2), which converts methylglyoxal into d-lactic acid in the presence of glutathione. Here we have shown that the two principal oxidative stress response pathways of Schizosaccharomyces pombe, Sty1 and Pap1, are involved in the response to methylglyoxal toxicity. The mitogen-activated protein kinase Sty1 is phosphorylated and accumulates in the nucleus following methylglyoxal treatment. Moreover, glo2 expression is induced by methylglyoxal and environmental stresses in a Sty1-dependent manner. The transcription factor Pap1 also accumulates in the nucleus, activating the expression of its target genes following methylglyoxal treatment. Our studies showed that the C-terminal cysteine-rich domain of Pap1 is sufficient for methylglyoxal sensing. Furthermore, the redox status of Pap1 is not changed by methylglyoxal. We propose that methylglyoxal treatment triggers Pap1 and Sty1 nuclear accumulation, and we describe the molecular basis of such activation mechanisms. In addition, we discuss the potential physiological significance of these responses to a natural toxic metabolite.
Highlights
Both Pap1 and Sty1 activities are regulated primarily by signal-dependent changes in subcellular localization
Resistance to MG Is Impaired in Mutants of the Pap1 and Sty1 Stress Pathways—The glyoxalase system is encoded in S. pombe by glo1 [20] and most likely by SPAC824.07/glo2 [21]
We examined whether the Sty1 and Pap1 pathways contributed to S. pombe cell susceptibility to MG
Summary
Both Pap1 and Sty1 activities are regulated primarily by signal-dependent changes in subcellular localization. Alkylation of any of the three cysteine residues at the C-CRD following treatment with DEM, or formation of a disulfide bond between Cys-278 at the N-CRD and Cys-501 or Cys-532 at the C-CRD in response to H2O2, can mask the accessibility of the nuclear exporter Crm1 to the C-terminal nuclear export signal (NES) of Pap1 and trigger its nuclear accumulation as well as Pap1-dependent gene expression [9, 10]. The YAP1 transcription factor, a homologue to Pap1 in S. pombe, is activated by MG (either by extracellular medium containing the natural metabolite or by increased intracellular MG in a ⌬glo1 strain) [12].
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