HDAC6-ubiquitin interaction controls the duration of HSF1 activation after heat shock.
Bottom Line: Here we show that a full response to heat shock (activation of both HSP70 and HSP25) depends on the duration of HSF1 activation, which is itself controlled by HDAC6, a unique deacetylase known to bind monoubiquitin and polyubiquitin with high affinity.In cells expressing HDAC6 mutated in the ubiquitin-binding domain, the AAA ATPase factor p97/VCP mediates rapid inactivation of HSF1, precluding late activation of the HSP25 gene.In these cells, knockdown of p97/VCP rescues HSF1 from this rapid inactivation and restores HSP25 expression.
Affiliation: University Grenoble-Alpes, CRI INSERM, U823, Institut Albert Bonniot, La Tronche 38042, Grenoble Cedex 9, France.Show MeSH
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Mentions: The ubiquitin-binding domain of HDAC6 protects cells against stress-induced apoptosis. Because HSP25 is well known for its role in cell protection against stress-induced apoptosis (Huot et al., 1991; Lee et al., 2004), we next sought to determine whether down-regulation of HSP25 in Ubm HDAC6–expressing cells would have a negative effect on cell protection against heat-induced apoptosis. We thus measured and compared the percentage of apoptotic cells in wild-type cells and in HDAC6 mutant–expressing cells submitted or not to a heat shock followed by recovery of 12 and 24 h at 37°C (Figure 6A). As expected, the percentage of apoptotic cells 24 h after heat shock was significantly higher (35-fold increase) in HDAC6 Ubm–expressing cells than in unstressed wild-type cells and three times higher than in all other cell lines at the same time point. These results confirm the importance of the ubiquitin-binding domain of HDAC6 in the HSP25-mediated protection of cells against cell death.
Affiliation: University Grenoble-Alpes, CRI INSERM, U823, Institut Albert Bonniot, La Tronche 38042, Grenoble Cedex 9, France.