The Heat Shock Response in Yeast Maintains Protein Homeostasis by Chaperoning and Replenishing Proteins

Abstract

Summary: Life is resilient because living systems are able to respond to elevated temperatures with an ancient gene expression program called the heat shock response (HSR). In yeast, the transcription of hundreds of genes is upregulated at stress temperatures. Besides stress protection conferred by chaperones, the function of the majority of the upregulated genes under stress has remained enigmatic. We show that those genes are required to directly counterbalance increased protein turnover at stress temperatures and to maintain the metabolism. This anaplerotic reaction together with molecular chaperones allows yeast to efficiently buffer proteotoxic stress. When the capacity of this system is exhausted at extreme temperatures, aggregation processes stop translation and growth pauses. The emerging concept is that the HSR is modular with distinct programs dependent on the severity of the stress. : Mühlhofer et al. show that under mild and severe heat stress, proteins lost due to increased aggregation and degradation are replenished by increased protein synthesis to ensure a constant pool of proteins, together with the molecular chaperones. The heat shock response is activated in modules by transcriptional regulation. Keywords: heat shock response, protein aggregation, chaperones, transcriptome, translatome, proteome, S. cerevisiae, ribosome profiling, mass spectrometry