Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity.

Ke Tan,Mitsuaki Fujimoto,Eiichi Takaki,Naoki Hayashida,Akira Nakai,Ryosuke Takii

doi:10.1038/ncomms7580

Abstract

Heat-shock response is an adaptive response to proteotoxic stresses including heat shock, and is regulated by heat-shock factor 1 (HSF1) in mammals. Proteotoxic stresses challenge all subcellular compartments including the mitochondria. Therefore, there must be close connections between mitochondrial signals and the activity of HSF1. Here, we show that heat shock triggers nuclear translocation of mitochondrial SSBP1, which is involved in replication of mitochondrial DNA, in a manner dependent on the mitochondrial permeability transition pore ANT–VDAC1 complex and direct interaction with HSF1. HSF1 recruits SSBP1 to the promoters of genes encoding cytoplasmic/nuclear and mitochondrial chaperones. HSF1–SSBP1 complex then enhances their induction by facilitating the recruitment of a chromatin-remodelling factor BRG1, and supports cell survival and the maintenance of mitochondrial membrane potential against proteotoxic stresses. These results suggest that the nuclear translocation of mitochondrial SSBP1 is required for the regulation of cytoplasmic/nuclear and mitochondrial proteostasis against proteotoxic stresses.

Highlights

Heat-shock response is an adaptive response to proteotoxic stresses including heat shock, and is regulated by heat-shock factor 1 (HSF1) in mammals
GST pull-down assay showed that recombinant GST fused to human HSF1 (GST-hHSF1) and a polyhistidine-tagged mouse SSBP1 interacted directly with each other, and the trimerization domain (HR-A/B) of hHSF1 was required for the interaction (Fig. 1b)
We found that the induction of mtHSP70 expression during heat shock was strictly dependent on SSBP1 as well as HSF1, and the recruitment of BRG1 was reduced in the presence of the HSF1 mutants (Supplementary Fig. 7c,d)

Summary

Introduction

Heat-shock response is an adaptive response to proteotoxic stresses including heat shock, and is regulated by heat-shock factor 1 (HSF1) in mammals. To deal with proteotoxic stresses, the cells have evolved sophisticated mechanisms accompanied by changes in gene expression, which adjust proteostasis capacity or buffering capacity against protein misfolding, at the level of protein synthesis, folding and degradation They include the heat-shock response (HSR) in the cytoplasm/nucleus and the unfolded-protein response (UPR) in the endoplasmic reticulum and mitochondria[2,3,4]. Mitochondrial chaperones and proteases, which are encoded in the genome, are induced during the accumulation of misfolded proteins within the mitochondrial matrix[18,19] This pathway of mitochondrial UPR is regulated by the transcription factor ATFS-1 in Caenorhabditis elegans, which is imported into the mitochondrial matrix under normal conditions and targeted to the nucleus in response to mitochondrial stresses[20]. The HSF1–SSBP1 complex supported cell survival and mitochondrial function in proteotoxic stress conditions

Methods

Results

Conclusion