Interplay of Acetyltransferase EP300 and the Proteasome System in Regu-Session 1

Presented by

Mirko Theis & Christian Loew

About this talk

In the present study, a genome-wide RNA interference screen was combined with an extensive biochemical analysis and quantitative proteomics to better understand the regulation of the heat-shock response (HSR) upon thermal stress. The usage of an endoribonuclease-prepared small interfering RNA (esiRNA) library represented a simple and efficient way to perform RNAi with minimal off-target effects. In the screening experiments novel positive and negative modulators of the stress response were identified, including proteins involved in chromatin remodeling, transcription, mRNA splicing, DNA damage repair, and proteolytic degradation. The diversity of the identified regulators suggests that induction and attenuation of the HSR integrate signals from different cellular pathways and are rather multi-factorial processes than single gene/protein events. The modulator proteins are localized in multiple cellular compartments with the majority having their primary location in the nucleus. A protein-protein interaction analysis revealed a HSR regulatory network, with chromatin modifiers and nuclear protein quality control components occupying hub positions. These observations are supported by quantitative proteomics experiments, which showed specific stress-induced reorganizations of the nuclear proteome, including the transient accumulation of chaperones and proteasomal subunits. Moreover, we found that the acetyltransferase EP300 controls the cellular level of activatable HSF1. This involves acetylation of HSF1 at multiple lysines not required for function and results in stabilization of HSF1 against proteasomal turnover. Acetylation of functionally critical lysines during stress serves to fine-tune HSF1 activation. Finally, the nuclear proteasome system functions in attenuating the stress response by degrading activated HSF1 in a manner linked with the clearance of misfolded proteins.

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