p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain.
ATF4 plays a crucial role in the cellular response to stress and multiple stress responses pathways converge to the translational up-regulation of ATF4. ATF4 is a substrate of the SCF(betaTrCP) ubiquitin ligase that binds to betaTrCP through phosphorylation on a DSGXXXS motif. We show here that ATF4 stability is also modulated by the histone acetyltransferase p300, which induces ATF4 stabilization by inhibiting its ubiquitination. Despite p300 acetylates ATF4, we found that p300-mediated ATF4 stabilization is independent of p300 catalytic activity, using either the inactive form of p300 or the acetylation mutant ATF4-K311R. ATF4 deleted of its p300 binding domain is no more stabilized by p300 nor recruited into nuclear speckles. In consequence of ATF4 stabilization, both p300 and the catalytically inactive enzyme increase ATF4 transcriptional activity.
Lassot
Irina
I
Institut Cochin, Department of Maladies Infectieuses, INSERM U567, CNRS UMR8104, University Rene Descartes Paris V, Bat G. Roussy, 27 Rue du Faubourg Saint Jacques, 75014 Paris, France.
Estrabaud
Emilie
E
Emiliani
Stephane
S
Benkirane
Monsef
M
Benarous
Richard
R
Margottin-Goguet
Florence
F
D051701:Activating Transcription Factor 4 / Q000737:chemistry*; D020816:Amino Acid Motifs; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000737:chemistry / Q000502:physiology*; D002384:Catalysis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D020868:Gene Silencing; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000737:chemistry* / Q000378:metabolism
C497109:ATF4 protein, human; D034741:RNA, Small Interfering; D025801:Ubiquitin; D051701:Activating Transcription Factor 4; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors; D005982:Glutathione Transferase