Abstract
The glucocorticoid receptor (GR) is essential for the stress response in mammals. We investigated potential non-transcriptional roles of GR in cellular stress response using fission yeast as a model.We surprisingly discovered marked heat stress resistance in yeast ectopically expressing human GR, which required expression of both the N-terminal transactivation domain, and the C-terminal ligand binding domain, but not the DNA-binding domain of the GR. This effect was not affected by GR ligand exposure, and occurred without significant GR nuclear accumulation. Mechanistically, the GR survival effect required Hsp104, and, indeed, GR expression increased Hsp104 expression. Proteomic analysis revealed GR binding to translasome components, including eIF3, a known partner for Sty1, a pattern of protein interaction which we confirmed using yeast two-hybrid studies.Taken together, we find evidence for a novel pathway conferring stress resistance in yeast that can be activated by the human GR, acting by protein-protein mechanisms in the cytoplasm. This suggests that in organisms where GR is natively expressed, GR likely contributes to stress responses through non-transcriptional mechanisms in addition to its well-established transcriptional responses.
Highlights
The glucocorticoid receptor is a member of the nuclear receptor superfamily, an ancient class of intracellular receptors that has dwindled in number through evolution (NURSA)[1]
The fission yeast S. pombe is evolutionarily divergent from S. cerevisiae[4,5]; in particular the stress-activated MAP kinase pathway is far closer to the mammalian orthologue than is the S. cerevisiae[6], and glucocorticoid receptor (GR) can serve as an active transcription factor in S. pombe if expressed with an appropriate reporter gene, indicating that the GR can be expressed, and retains function[7]
We identified an unexpected role for the translasome[8,9], with GR interacting with key components in the cytoplasm
Summary
The glucocorticoid receptor is a member of the nuclear receptor superfamily, an ancient class of intracellular receptors that has dwindled in number through evolution (NURSA)[1]. As natural selection in evolution can select for function, and not sequence, we ectopically expressed the human GR in the fission yeast Schizosaccharomyces pombe (S. pombe) to test the hypothesis that non-genomic GR signalling is functionally conserved through evolution. The fission yeast S. pombe is evolutionarily divergent from S. cerevisiae[4,5]; in particular the stress-activated MAP kinase pathway is far closer to the mammalian orthologue than is the S. cerevisiae[6], and GR can serve as an active transcription factor in S. pombe if expressed with an appropriate reporter gene, indicating that the GR can be expressed, and retains function[7]. We sought to identify a non-genomic signalling role for the GR when expressed ectopically in S. pombe. We found that ectopic GR conferred heat shock resistant to the S. pombe, through a cytoplasmic, non-genomic mechanism. We identified an unexpected role for the translasome[8,9], with GR interacting with key components in the cytoplasm
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