CBP/EP300 acetylates and stabilizes the stress-responsive Heat Shock Factor 2, a process compromised in Rubinstein-Taybi syndrome

that CBP/EP300 mediates the acetylation of HSF2 on specific lysine residues, through critical interaction between the CBP-KIX domain and the HSF2 oligomerisation domain, thereby promoting the stabilization of the HSF2 protein. We then interrogate the functional importance of this regulation in the pathological context of RSTS. We observe a proteasomal-dependent reduction in HSF2 protein levels in cells derived from RSTS patients, which results in impairement of their ability to mount a proper heat shock response. The disruption of the HSR pathway in RSTS highlights the importance of the CBP/EP300-dependent regulation of HSF2 by acetylation and provides a new conceptual frame for understanding the molecular basis of this complex pathology.

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