HSFs’ activity is primarily regulated by various post-translational modifications (PTMs), e.g. acetylation, phosphorylation, sumoylation, and ubiquitilation. All these PTMs are induced by stress stimuli, but their effects on HSFs vary. Phosphorylation is a hallmark PTM of HSF1, and to date, 23 phosphorylation sites have been found. Stress-inducible phosphorylation of HSF1 (hyperphosphorylation) coincides with the acquisition of HSF1 trans-activation capacity. Hyperphosphorylation has been considered as a prerequisite for HSF1’s function as a transcription factor. However, we have recently shown that a change in the phosphorylation status is not required for the activation of HSF1 but serves as a modulatory mechanism of the transcriptionally competent HSF1.
Upon stress, HSF1 undergoes phosphorylation-dependent sumoylation within a bipartite motif, which is called PDSM (phosphorylation-dependent sumoylation motif) and found in many transcriptional regulators. Phosphorylation-dependent sumoylation of HSF1 leads to repression of its trans-activation capacity, and duration of SUMO conjugation to HSF1 correlates with severity of stress. Interestingly, our results indicate that the persistence of SUMO conjugation to HSF1 functions as a stress-sensitive barrier that restrains HSF1 activity upon moderate stress.
Stress-inducible hyperphosphorylation and sumoylation of HSF1 occur very rapidly, whereas its acetylation increases gradually, suggesting a role for acetylation in the attenuation phase of the HSF1 activity cycle. Among multiple lysine residues, acetylation of K80, within the DNA-binding domain, has an inhibitory effect on the DNA-binding activity of HSF1. Importantly, the duration of HSF1 DNA-binding activity can be prolonged or diminished by chemical compounds, either activating or inhibiting the activity of the NAD+-dependent deacetylase SIRT1.
HSF2 is subjected to ubiquitilation and sumoylation. Upon stress, HSF2 is ubiquitilated rapidly by the E3 ligase anaphase-promoting complex/cyclosome (APC/C), which leads to HSF2 degradation by the proteasome. Sumoylation of K82 reduces the DNA-binding activity of HSF2, but the regulatory mechanism for this PTM remains to be elucidated.
A plethora of PTMs provide fine-tuning mechanisms for controlling the activity of HSFs under various conditions. We aim at identifying the specific PTM signatures of HSFs, since PTMs likely contribute to the distinct HSF-driven transcriptional programs in development, cell stress and disease.
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