Department of Environmental Medicine, University of Rochester Medical Center, NY 14642, USA.
Arch Biochem Biophys. 2010 Jun 1;498(1):62-73. doi: 10.1016/j.abb.2010.04.002. Epub 2010 Apr 11.
Histone deacetylase 2 (HDAC2) mediates the repression of pro-inflammatory genes by deacetylating core histones, RelA/p65 and the glucocorticoid receptor. Reduced level of HDAC2 is associated with steroid resistant inflammation caused by cigarette smoke (CS)-derived oxidants and aldehydes. However, the molecular mechanisms regulating HDAC2 in response to CS and aldehydes is not known. Here, we report that CS extract, and aldehyde acrolein induced phosphorylation of HDAC2 which was abolished by mutations at serine sites S(394), S(411), S(422) and S(424). HDAC2 phosphorylation required direct interaction with serine-phosphorylated protein kinase CK2alpha and involved reduced HDAC2 deacetylase activity. Furthermore, HDAC2 phosphorylation was required for HDAC2 interaction with transcription factors, co-repressor complex formation, CBP recruitment, acetylation on lysine residues and modulates transrepression activity. Thus, phospho-acetylation of HDAC2 negatively regulates its deacetylase activity which has implications in steroid resistance in chronic inflammatory conditions.
组蛋白去乙酰化酶 2（HDAC2）通过去乙酰化核心组蛋白、RelA/p65 和糖皮质激素受体来介导促炎基因的抑制。HDAC2 水平降低与香烟烟雾（CS）衍生的氧化剂和醛引起的类固醇耐药性炎症有关。然而，调节 CS 和醛对 HDAC2 的分子机制尚不清楚。在这里，我们报告 CS 提取物和醛丙烯醛诱导 HDAC2 的磷酸化，该磷酸化在丝氨酸位点 S(394)、S(411)、S(422)和 S(424)发生突变时被消除。HDAC2 磷酸化需要与丝氨酸磷酸化蛋白激酶 CK2alpha 的直接相互作用，并涉及降低的 HDAC2 去乙酰化酶活性。此外，HDAC2 磷酸化是 HDAC2 与转录因子相互作用、共抑制复合物形成、CBP 募集、赖氨酸残基乙酰化和调节转录抑制活性所必需的。因此，HDAC2 的磷酸化-乙酰化负调节其去乙酰化酶活性，这对慢性炎症条件下的类固醇耐药性有影响。
