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.


Functional Domains and PTMs of HSF1 and HSF2. HSFs share similar functional domains and undergo extensive post-translational modifications (PTMs). Schematic illustrations of human HSF1 (hHSF1) and HSF2 (hHSF2) with the known post-translationally modified amino acids indicated. HR-A/B/C – leucin-zipper-like heptad-repeat domains. The last amino acid of each protein is indicated. Note that the figure is not drawn to scale.

Selected publications:

Uncoupling stress-inducible phosphorylation of heat shock factor 1 from its activation.
Budzyński MA, Puustinen MC, Joutsen J, Sistonen L.
Mol Cell Biol. 2015 Jul;35(14):2530-40.

Anaphase-promoting complex/cyclosome participates in the acute response to protein-damaging stress.
Ahlskog JK, Björk JK, Elsing AN, Aspelin C, Kallio M, Roos-Mattjus P, Sistonen L.
Mol Cell Biol. 2010 Dec;30(24):5608-20.

Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1.
Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI.
Science. 2009 Feb 20;323(5917):1063-6.

PDSM, a motif for phosphorylation-dependent SUMO modification.
Hietakangas V, Anckar J, Blomster HA, Fujimoto M, Palvimo JJ, Nakai A, Sistonen L.
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):45-50.

Inhibition of DNA binding by differential sumoylation of heat shock factors.
Anckar J, Hietakangas V, Denessiouk K, Thiele DJ, Johnson MS, Sistonen L.
Mol Cell Biol. 2006 Feb;26(3):955-64.

Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1.
Holmberg CI, Hietakangas V, Mikhailov A, Rantanen JO, Kallio M, Meinander A, Hellman J, Morrice N, MacKintosh C, Morimoto RI, Eriksson JE, Sistonen L.
EMBO J. 2001 Jul 16;20(14):3800-10.