1. CBP/EP300-dependent acetylation and stabilization of HSF2 are compromised in the rare disorder, Rubinstein-Taybi syndrome
- Author
-
Carène Benasolo, Élise Lebigot, Jérémy Berthelet, Madeline A. Lancaster, Federico Miozzo, Didier Lacombe, Sarah Naceri, Déborah Bouvier, Olivier Taboureau, Aurélie de Thonel, Johanna K. Ahlskog, Véronique Dubreuil, Mathilde Henry, Pierre Gressens, Sandrine Passemart, Matthieu Sanial, Jean-Paul Concordet, Délara Sabéran-Djoneidi, Patricia Fergelot, Marion Cordonnier, Jessica Gobbo, Mikael C. Puustinen, Anna L. Aalto, Agathe Duchateau, Michel Petitjean, Ryma Abane, Alain Verloes, Lea Sistonen, Carmen Garrido, Valérie Mezger, Sandy D. Westerheide, Anniina Vihervaara, Fernando Rodrigues-Uma, and Geoffrey Pires
- Subjects
0303 health sciences ,Chemistry ,In silico ,Human brain ,HDAC1 ,3. Good health ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Proteostasis ,Acetylation ,medicine ,Heat shock ,EP300 ,Transcription factor ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
SUMMARYCells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcription factors of proteostasis. Abnormal HSF protein levels occur in cancer and neurodegenerative disorders, highlighting the importance of the tight control of HSF expression. HSF2 is a short-lived protein, but it is abundant in the prenatal brain cortex and required for brain development. Here, we reveal that HSF2 is acetylated and co-localized with the lysine-acetyl transferases CBP and EP300 in human brain organoids. Using unbiased, biochemical, cell-imaging, and in silico approaches, we show that CBP/EP300 acetylates HSF2 at specific lysine residues, which promotes HSF2 stabilization, whereas the lysine deacetylase HDAC1 catalyzes its proteasomal degradation. The CBP KIX domain and KlX-recognizing motifs in HSF2 are critical for its interaction with acetylating enzymes. The functional importance of acetylated HSF2 is evidenced in Rubinstein-Taybi syndrome (RSTS), characterized by mutated CBP or EP300. We show that RSTS patient cells exhibit decreased HSF2 levels and impaired heat shock response. The dysregulated HSF pathway in RSTS opens new avenues for understanding the molecular basis of this multifaceted pathology.
- Published
- 2018
- Full Text
- View/download PDF