Histone Deacetylase 2 Is Phosphorylated, Ubiquitinated, and Degraded by Cigarette Smoke
Histone Deacetylase 2 Is Phosphorylated, Ubiquitinated, and Degraded by Cigarette Smoke
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DOI：
10.1165/rcmb.2008-0255oc
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发表时间：
2009-04-01
影响因子：
6.4
通讯作者：
Rahman, Irfan
中科院分区：
文献类型：
--
作者：
Adenuga, David;Yao, Hongwei;Rahman, Irfan
香烟烟雾（CS）诱导的肺部炎症涉及组蛋白去乙酰化酶2（HDAC 2）丰度的减少，这与慢性阻塞性肺疾病患者和吸烟的严重哮喘患者的类固醇抵抗有关。然而，CS介导的HDAC 2减少的分子机制尚不清楚。我们假设HDAC 2被磷酸化，随后在体外被巨噬细胞（MonoMac 6）、人支气管和原代小气道上皮细胞中的蛋白酶体降解，在体内被小鼠肺中的蛋白酶体降解，以响应慢性CS暴露。香烟烟雾提取物（CSE）暴露在MonoMac 6和支气管和气道上皮细胞中导致HDAC 2的丝氨酸/苏氨酸残基的磷酸化通过蛋白激酶CK 2介导的机制，降低HDAC 2活性，并增加泛素-蛋白酶体依赖性HDAC 2降解。CK 2和蛋白酶体抑制剂逆转CSE介导的HDAC 2降解，而丝氨酸/苏氨酸磷酸酶抑制剂冈田酸引起HDAC 2的磷酸化和随后的泛素化。CS暴露2周到4个月期间，在小鼠肺部检测到CS诱导的HDAC 2磷酸化，并且小鼠的肺部HDAC 2水平显着降低。因此，CS介导的HDAC 2在体外人巨噬细胞和肺上皮细胞中以及在体内小鼠肺中的下调涉及丝氨酸/苏氨酸磷酸化和蛋白酶体降解的诱导，这可能与香烟烟雾引起的类固醇抗性和异常炎症有关。
Cigarette smoke (CS)-induced lung inflammation involves the reduction of histone deacetylase 2 (HDAC2) abundance, which is associated with steroid resistance in patients with chronic obstructive pulmonary disease and in individuals with severe asthma who smoke cigarettes. However, the molecular mechanism of CS-mediated reduction of HDAC2 is not clearly known. We hypothesized that HDAC2 is phosphorylated and subsequently degraded by the proteasome in vitro in macrophages (MonoMac6), human bronchial and primary small airway epithelial cells, and in vivo in mouse lungs in response to chronic CS exposure. Cigarette smoke extract (CSE) exposure in MonoMac6 and in bronchial and airway epithelial cells led to phosphorylation of HDAC2 on serine/threonine residues by a protein kinase CK2-mediated mechanism, decreased HDAC2 activity, and increased ubiquitin-proteasome-dependent HDAC2 degradation. CK2 and proteasome inhibitors reversed CSE-mediated HDAC2 degradation, whereas serine/threonine phosphatase inhibitor, okadaic acid, caused phosphorylation and subsequent ubiquitination of HDAC2. CS-induced HDAC2 phosphorylation was detected in mouse lungs from 2 weeks to 4 months of CS exposure, and mice showed significantly lower lung HDAC2 levels. Thus, CS-mediated down-regulation of HDAC2 in human macrophages and lung epithelial cells in vitro and in mouse lung in vivo involves the induction of serine/threonine phosphorylation and proteasomal degradation, which may have implications for steroid resistance and abnormal inflammation caused by cigarette smoke.