HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates
- Cyril Boyault1,2,7,
- Yu Zhang3,7,
- Sabrina Fritah1,2,7,
- Cécile Caron1,2,
- Benoit Gilquin1,2,
- So Hee Kwon3,
- Carmen Garrido4,5,
- Tso-Pang Yao6,
- Claire Vourc’h1,2,
- Patrick Matthias3, and
- Saadi Khochbin1,2,8
- 1 Institut National de la Santé et de la Recherche Médicale (INSERM), U823, Institut Albert Bonniot, Grenoble F-38706, France;
- 2 Université Joseph Fourier, Institut Albert Bonniot, Grenoble F-38700, France;
- 3 Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, 4058 Basel, Switzerland;
- 4 INSERM, U517, Dijon F-21079, France;
- 5 Université de Bourgogne, Faculté de Médecine de Dijon, Dijon F-21079, France;
- 6 Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA
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↵7 These authors contributed equally to this work.
Abstract
A cellular defense mechanism counteracts the deleterious effects of misfolded protein accumulation by eliciting a stress response. The cytoplasmic deacetylase HDAC6 (histone deacetylase 6) was previously shown to be a key element in this response by coordinating the clearance of protein aggregates through aggresome formation and their autophagic degradation. Here, for the first time, we demonstrate that HDAC6 is involved in another crucial cell response to the accumulation of ubiquitinated protein aggregates, and unravel its molecular basis. Indeed, our data show that HDAC6 senses ubiquitinated cellular aggregates and consequently induces the expression of major cellular chaperones by triggering the dissociation of a repressive HDAC6/HSF1 (heat-shock factor 1)/HSP90 (heat-shock protein 90) complex and a subsequent HSF1 activation. HDAC6 therefore appears as a master regulator of the cell protective response to cytotoxic protein aggregate formation.
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Footnotes
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↵8 Corresponding author.
↵8 E-MAIL khochbin@ujf-grenoble.fr; FAX 33-4-76-54-95-95.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.436407
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- Received April 10, 2007.
- Accepted July 13, 2007.
- Copyright © 2007, Cold Spring Harbor Laboratory Press