1] Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, Melbourne, Victoria 3168, Australia.
Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
Nat Commun. 2015 Apr 13;6:6795. doi: 10.1038/ncomms7795.
To date, the activities of protein kinases have formed the core of our understanding of cell signal transduction. Comprehension of the extent of protein acetylation has raised expectations that this alternate post-transcriptional modification will be shown to rival phosphorylation in its importance in mediating cellular responses. However, limited instances have been identified. Here we show that signalling from Toll-like or TNF-α receptors triggers the calcium/calmodulin-dependent protein kinase (CaMK2) to activate histone acetyltransferase-1 (HAT1), which then acetylates the transcriptional regulator PLZF. Acetylation of PLZF promotes the assembly of a repressor complex incorporating HDAC3 and the NF-κB p50 subunit that limits the NF-κB response. Accordingly, diminishing the activity of CaMK2, the expression levels of PLZF or HAT1, or mutating key residues that are covalently modified in PLZF and HAT1, curtails control of the production of inflammatory cytokines. These results identify a central role for acetylation in controlling the inflammatory NF-κB transcriptional programme.
迄今为止，蛋白激酶的活性已经成为我们理解细胞信号转导的核心。对蛋白质乙酰化程度的理解使人们产生了这样的期望，即这种转录后修饰方式将与磷酸化在介导细胞反应的重要性相媲美。然而，目前只发现了有限的例子。在这里，我们表明 Toll 样受体或 TNF-α 受体发出的信号会触发钙/钙调蛋白依赖性蛋白激酶（CaMK2）激活组蛋白乙酰转移酶-1（HAT1），然后 HAT1 乙酰化转录调节因子 PLZF。PLZF 的乙酰化促进了包含 HDAC3 和 NF-κB p50 亚基的抑制复合物的组装，从而限制了 NF-κB 的反应。因此，降低 CaMK2 的活性、PLZF 或 HAT1 的表达水平，或突变 PLZF 和 HAT1 中被共价修饰的关键残基，都会限制炎症细胞因子的产生。这些结果表明乙酰化在控制炎症 NF-κB 转录程序中起着核心作用。
