CBP/EP300-dependent acetylation and stabilization of HSF2 are compromised in the rare disorder, Rubinstein-Taybi syndrome

Cells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcription factors of proteostasis. Abnormal levels of HSFs occur in cancer and neurodegenerative disorders, highlighting the strict control of their expression. HSF2 is a short-lived protein, which is abundant in the prenatal brain cortex and required for brain development. Here, we report that HSF2 is acetylated and co-localized with the lysine-acetyl transferases CBP and EP300 in human brain organoids. CBP/EP300 mediates the acetylation of HSF2 on specific lysine residues, through critical interaction between the CBP-KIX domain and the HSF2 oligomerisation domain, and promotes HSF2 stabilization. The functional importance of acetylated HSF2 is evidenced in Rubinstein-Taybi syndrome (RSTS), characterized by mutated CBP or EP300. We show that cells derived from RSTS patients 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.