Fig. 2
From: The heat shock response in neurons and astroglia and its role in neurodegenerative diseases
The activation of HSF1 and its binding to DNA is regulated by a multi-step pathway that involves nuclear accumulation, intramolecular and intermolecular protein interactions, and post-translational modifications. (1) In the absence of stress, HSF1 is maintained in a monomeric state through the regulatory actions of several post-translational modifications, intramolecular contacts, and interactions with Hsps in inhibitory complexes. Cellular stress results in the accumulation of misfolded and damaged proteins, which compete with HSF1 for binding to Hsps. (2) HSF1 monomers are released and undergo a conformational change conducive to trimerization. (3) Concurrent nuclear accumulation, HSE-binding and hyperphosphorylation of trimeric HSF1 occur. (4) This process releases RNA PolII from a paused to an active state to initiate the transcription of stress-induced genes. (5) SUMOylation at K298 and binding of Hsp40/Hsp70 represses the transcriptional activity of HSF1 trimers. (6) Acetylation at K80 disrupts HSF1 binding to DNA and HSF1 trimers dissociate and re-join the monomeric pool in the cytosol. Stress-inducible Hsps participate in a negative-feedback loop to inhibit further HSF1 activation