Lassot Irina, Estrabaud Emilie, Emiliani Stephane, Benkirane Monsef, Benarous Richard, Margottin-Goguet Florence
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.
J Biol Chem. 2005 Dec 16;280(50):41537-45. doi: 10.1074/jbc.M505294200. Epub 2005 Oct 11.
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.
ATF4在细胞对应激的反应中起关键作用，多种应激反应途径会汇聚到ATF4的翻译上调。ATF4是SCF(βTrCP)泛素连接酶的底物，它通过DSGXXXS基序上的磷酸化与βTrCP结合。我们在此表明，ATF4的稳定性也受到组蛋白乙酰转移酶p300的调节，p300通过抑制其泛素化来诱导ATF4稳定。尽管p300使ATF4乙酰化，但我们发现，使用p300的无活性形式或乙酰化突变体ATF4-K311R，p300介导的ATF4稳定与p300的催化活性无关。缺失其p300结合结构域的ATF4不再被p300稳定，也不会被招募到核斑点中。由于ATF4稳定，p300和催化无活性的酶都会增加ATF4的转录活性。
