Heat shock protein 27 is involved in SUMO-2/3 modification of heat shock factor 1 and thereby modulates the transcription factor activity

Abstract

Heat shock protein 27 (HSP27) accumulates in stressed cells and helps them to survive adverse conditions. We have already shown that HSP27 has a function in the ubiquitination process that is modulated by its oligomerization/phosphorylation status. Here, we show that HSP27 is also involved in protein sumoylation, a ubiquitinationrelated process. HSP27 increases the number of cell proteins modified by small ubiquitin-like modifier (SUMO)-2/3 but this effect shows some selectivity as it neither affects all proteins nor concerns SUMO-1. Moreover, no such alteration in SUMO-2/3 conjugation is achievable by another HSP, such as HSP70. Heat shock factor 1 (HSF1), a transcription factor responsible for HSP expression, is one of the targets of HSP27. In stressed cells, HSP27 enters the nucleus and, in the form of large oligomers, binds to HSF1 and induces its modification by SUMO-2/3 on lysine 298. HSP27-induced HSF1 modification by SUMO-2/3 takes place downstream of the transcription factor phosphorylation on S303 and S307 and does not affect its DNA-binding ability. In contrast, this modification blocks HSF1 transactivation capacity. These data show that HSP27 exerts a feedback inhibition of HSF1 transactivation and enlighten the strictly regulated interplay between HSPs and HSF1. As we also show that HSP27 binds to the SUMO-E2-conjugating enzyme, Ubc9, our study raises the possibility that HSP27 may act as a SUMO-E3 ligase specific for SUMO-2/3.

Heat Shock Protein as Molecular Targets for Breast Cancer Therapeutics

“…HSP27 can be phosphorylated at three serine residues 15, 78, and 82, and its phosphorylation is mediated by the p38 MAPK stress kinase pathway [29]. This phosphorylation is a reversible event that modulates the oligomerization of HSP27.…”

Immense Cellular Implications Associated to Small Stress Proteins Expression: Impacts on Human Pathologies

“…HSF1 (heat shock factor 1), the transcription factor responsible for Hsps expression, has also been shown to play a crucial role in tumorogenesis (Mendillo et al 2012 ). HSF1 is SUMO-2/3 modifi ed by HspB1-Ubc9 complex (Brunet Simioni et al 2009 ). This modifi cation does not affect HSF1 DNA-binding ability but blocks its transactivation function suggesting that it could act, together with NuRD factors, as a transcriptional inhibitor that represses genes that oppose metastasis.…”

Metabolic control of the proteotoxic stress response: implications in diabetes mellitus and neurodegenerative disorders

“…For example, phosphorylation at Ser303 leads to sumoylation at Lys298 on HSF1, thereby suppressing its transcriptional activity [60, 61]. Moreover, sumoylation could mediate protein-protein interactions by providing a docking site for proteins containing small ubiquitin-like modifier (SUMO)-interacting motif [62, 63]. …”

“…In further support of the metabolic regulation of HSF1, other key metabolic sensors including SIRT1 and AMPK are able to modify HSF1 as well. AMPK phosphorylates and SIRT1 deacetylates HSF1, respectively [54, 63]. Congruently, high-fat diets impair AMPK-dependent phosphorylation of PGC-1α and increase the expression and activity of SIRT1, thereby activating HSF1 [94].…”