Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions

Abstract

Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technological limitations have so far prevented a global analysis of lysine acetylation's cellular roles. We used high-resolution mass spectrometry to identify 3600 lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other major posttranslational modifications.

The bromodomain interaction module

“…Although lysine acetylation has been studied for a long time in the context of the histone code it is now recognized as a widespread post-translational modification occurring throughout the proteome [11,12]. So far, 18330 sites on 6870 proteins have been reported in total in human cells in the PhosphoSitePlus database (http://www.phosphosite.org) suggesting a wider role for this PTM, highlighting its importance.…”

“…Given the wide distribution of acetylation in cells according to proteomics data analysis [11] it is surprising that mainly interactions between histones and BRDs have been extensively studied so far. There is evidence of interactions between BRDs and other 'hotspots' such as p53 [41,85] or transcription factors such as MyoD [62,63], RelA [51] and GATA1 [53,92].…”

Diversity within the pRb pathway: is there a code of conduct?

“…A recent study in which the scope of lysine acetylation at the proteome-wide level was examined revealed further sites of acetylation on pRb at K427, K548, K640, K653 and K896 (Choudhary et al, 2009). The functional relevance of these events awaits further investigation, but given that four of these residues are located in the vicinity of the pocket region of pRb it is possible that they could affect interactions with proteins that bind to the pRb pocket, with wide ranging consequences.…”

Epigenetic cancer therapy: rationales, targets and drugs

“…However, similar to the situation with DNA methyltransferase inhibitors, a direct link between druginduced histone hyperacetylation and clinical responses remains to be established. It is now becoming increasingly clear that the enzymatic activity of HDACs is not restricted to histone proteins, and treatment of human cancer cell lines with highly specific HDAC inhibitors can induce hyperacetylation of 1750 proteins (Choudhary et al, 2009). This finding strongly suggests that nonhistone proteins constitute the large majority of HDAC substrates.…”