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HDAC6-ubiquitin interaction controls the duration of HSF1 activation after heat shock.

Pernet L, Faure V, Gilquin B, Dufour-Guérin S, Khochbin S, Vourc'h C - Mol. Biol. Cell (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: University Grenoble-Alpes, CRI INSERM, U823, Institut Albert Bonniot, La Tronche 38042, Grenoble Cedex 9, France.

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General model illustrating the role of the ubiquitin-binding domain of HDAC6 in the control of the duration of HSF1 activation. In unstressed cells, HSF1 is present in a dormant complex involving HDAC6, p97/VCP, and HSPs. On heat shock, HDAC6 dissociates from HSF1 and binds to polyubiquitinylated (Poly-Ub) proteins, allowing HSF1 binding to HSP70 gene (early response). The activation of the late inducible HSP25 gene (late response) depends on the duration of HSF1 activation and on the quantity of Poly-Ub proteins allowing (high amount) or not (low amount) the sustained activation of HSF1 during the recovery period from stress. Reformation of the inactive HSF1 dormant complex occurs either when poly-Ub proteins are no longer available or when binding of HDAC6 to poly-Ub proteins cannot occur due to a mutation in the Ub-binding domain of HDAC6 (bottom). Reformation of the HSF1 inactive complex requires p97/VCP, whose binding to HDAC6 only occurs when free, poly-Ub unbound HDAC6 is available. In KO cells, absence of VCP-HDAC6 complex impairs reformation of the inactive HSF1 complex, resulting in sustained activation of HSF1 and accumulation of HSP25.
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Figure 5: General model illustrating the role of the ubiquitin-binding domain of HDAC6 in the control of the duration of HSF1 activation. In unstressed cells, HSF1 is present in a dormant complex involving HDAC6, p97/VCP, and HSPs. On heat shock, HDAC6 dissociates from HSF1 and binds to polyubiquitinylated (Poly-Ub) proteins, allowing HSF1 binding to HSP70 gene (early response). The activation of the late inducible HSP25 gene (late response) depends on the duration of HSF1 activation and on the quantity of Poly-Ub proteins allowing (high amount) or not (low amount) the sustained activation of HSF1 during the recovery period from stress. Reformation of the inactive HSF1 dormant complex occurs either when poly-Ub proteins are no longer available or when binding of HDAC6 to poly-Ub proteins cannot occur due to a mutation in the Ub-binding domain of HDAC6 (bottom). Reformation of the HSF1 inactive complex requires p97/VCP, whose binding to HDAC6 only occurs when free, poly-Ub unbound HDAC6 is available. In KO cells, absence of VCP-HDAC6 complex impairs reformation of the inactive HSF1 complex, resulting in sustained activation of HSF1 and accumulation of HSP25.

Mentions: In conclusion, our data reveal that p97/VCP is not critical for HSF1 activation in heat-shocked cells but plays an important role in the reformation of the inactive HSF1 complex. We found that VCP accelerates the reformation of the repressive HSF1 complex when binding of HDAC6 to ubiquitinated residues no longer occurs (Figure 5).


HDAC6-ubiquitin interaction controls the duration of HSF1 activation after heat shock.

Pernet L, Faure V, Gilquin B, Dufour-Guérin S, Khochbin S, Vourc'h C - Mol. Biol. Cell (2014)

General model illustrating the role of the ubiquitin-binding domain of HDAC6 in the control of the duration of HSF1 activation. In unstressed cells, HSF1 is present in a dormant complex involving HDAC6, p97/VCP, and HSPs. On heat shock, HDAC6 dissociates from HSF1 and binds to polyubiquitinylated (Poly-Ub) proteins, allowing HSF1 binding to HSP70 gene (early response). The activation of the late inducible HSP25 gene (late response) depends on the duration of HSF1 activation and on the quantity of Poly-Ub proteins allowing (high amount) or not (low amount) the sustained activation of HSF1 during the recovery period from stress. Reformation of the inactive HSF1 dormant complex occurs either when poly-Ub proteins are no longer available or when binding of HDAC6 to poly-Ub proteins cannot occur due to a mutation in the Ub-binding domain of HDAC6 (bottom). Reformation of the HSF1 inactive complex requires p97/VCP, whose binding to HDAC6 only occurs when free, poly-Ub unbound HDAC6 is available. In KO cells, absence of VCP-HDAC6 complex impairs reformation of the inactive HSF1 complex, resulting in sustained activation of HSF1 and accumulation of HSP25.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 5: General model illustrating the role of the ubiquitin-binding domain of HDAC6 in the control of the duration of HSF1 activation. In unstressed cells, HSF1 is present in a dormant complex involving HDAC6, p97/VCP, and HSPs. On heat shock, HDAC6 dissociates from HSF1 and binds to polyubiquitinylated (Poly-Ub) proteins, allowing HSF1 binding to HSP70 gene (early response). The activation of the late inducible HSP25 gene (late response) depends on the duration of HSF1 activation and on the quantity of Poly-Ub proteins allowing (high amount) or not (low amount) the sustained activation of HSF1 during the recovery period from stress. Reformation of the inactive HSF1 dormant complex occurs either when poly-Ub proteins are no longer available or when binding of HDAC6 to poly-Ub proteins cannot occur due to a mutation in the Ub-binding domain of HDAC6 (bottom). Reformation of the HSF1 inactive complex requires p97/VCP, whose binding to HDAC6 only occurs when free, poly-Ub unbound HDAC6 is available. In KO cells, absence of VCP-HDAC6 complex impairs reformation of the inactive HSF1 complex, resulting in sustained activation of HSF1 and accumulation of HSP25.
Mentions: In conclusion, our data reveal that p97/VCP is not critical for HSF1 activation in heat-shocked cells but plays an important role in the reformation of the inactive HSF1 complex. We found that VCP accelerates the reformation of the repressive HSF1 complex when binding of HDAC6 to ubiquitinated residues no longer occurs (Figure 5).

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.

View Article: PubMed Central - PubMed

Affiliation: University Grenoble-Alpes, CRI INSERM, U823, Institut Albert Bonniot, La Tronche 38042, Grenoble Cedex 9, France.

Show MeSH
Related in: MedlinePlus