HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates.
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.
Boyault
Cyril
C
Institut National de la Santé et de la Recherche Médicale (INSERM), U823, Institut Albert Bonniot, Grenoble F-38706, France.
Zhang
Yu
Y
Fritah
Sabrina
S
Caron
Cécile
C
Gilquin
Benoit
B
Kwon
So Hee
SH
Garrido
Carmen
C
Yao
Tso-Pang
TP
Vourc'h
Claire
C
Matthias
Patrick
P
Khochbin
Saadi
S
D016475:3T3 Cells; D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000502:physiology*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D014157:Transcription Factors / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein