Heat Shock Response

Heat shock genes encode molecular chaperones and other cytoprotective molecules that prevent accumulation of damaged proteins. In eukaryotes, synthesis of heat shock proteins (HSPs) is regulated primarily at the level of transcription by a master activator HSF1.

We identified a nucleoprotein complex, containing the translation elongation factor eEF1A1 and a non-coding RNA that is required for HSF1 activation. We also showed that eEF1A1 orchestrates the entire process of heat shock response (HSR), from the transcriptional activation of heat shock genes to the stabilization, transport, and translation of their mRNAs. We continue to investigate the complex mechanism of HSR at transcriptional and post-transcriptional levels.

The results of our studies will have implications for numerous physiological conditions associated with protein misfolding, including various types of cancer and neurodegenerative diseases.

eEF1A1 orchestrates the HSR process. Prior to stress, eEF1A1 is bound to HSP promoters and acts as a transcriptional repressor. Upon heat shock, eEF1A1 recruits HSF1 to the promoter thus activating transcription. HSF1 trimerization and DNA binding also depend on the eEF1A1-bound RNA cofactor (not shown), which presumably acts as a thermosensor. eEF1A1 then translocates along with transcribing RNAPII and binds HSP mRNA 3’ UTR, stabilizing the transcript and delivering it through the NPC to the ribosome. By synchronizing each major step of HSP gene expression, eEF1A1 matches the transcriptional output to translational needs for HSPs, making the overall process of HSR extremely robust and coordinated.