Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo.
The 70kDa ribosomal protein S6 kinases (S6K1 and S6K2) play important roles in the regulation of protein synthesis, cell growth and survival. S6Ks are activated in response to mitogen stimulation and nutrient sufficiency by the phosphorylation of conserved serine and threonine residues. Here we show for the first time, that in addition to phosphorylation, S6Ks are also targeted by lysine acetylation. Following mitogen stimulation, S6Ks interact with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300. Furthermore, it appears that the acetylation sites targeted by p300 lie within the divergent C-terminal regulatory domains of both S6K1 and S6K2. Acetylation of S6K1 and 2 is increased upon the inhibition of class I/II histone deacetylases (HDACs) by trichostatin-A, while the enhancement of S6K1 acetylation by nicotinamide suggests the additional involvement of sirtuin deacetylases in S6K deacetylation. Both expression of p300 and HDAC inhibition cause increases in S6K protein levels, and we have shown that S6K2 is stabilized in cells treated with HDAC inhibitors. The finding that S6Ks are targeted by histone acetyltransferases uncovers a novel mode of crosstalk between mitogenic signalling pathways and the transcriptional machinery and reveals additional complexity in the regulation of S6K function.
Fenton
T R
TR
Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.
Gwalter
J
J
Ericsson
J
J
Gout
I T
IT
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D051548:Histone Acetyltransferases; D006657:Histones; D008239:Lysine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor