Histone 3.3 Participates in a Self-Sustaining Cascade of Apoptosis That Contributes to the Progression of Chronic Obstructive Pulmonary Disease
Histone 3.3 Participates in a Self-Sustaining Cascade of Apoptosis That Contributes to the Progression of Chronic Obstructive Pulmonary Disease
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DOI：
10.1164/rccm.201302-0342oc
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发表时间：
2013-09-15
影响因子：
24.7
通讯作者：
Merali, Salim
中科院分区：
文献类型：
--
作者：
Barrero, Carlos A.;Perez-Leal, Oscar;Merali, Salim
理由：慢性阻塞性肺疾病（COPD）是一种以广泛的肺部炎症和细胞凋亡为特征的进行性疾病，其核蛋白基因表达的变化是常见的；然而，核心组蛋白（核蛋白的主要成分）的升高程度及其在COPD中的影响尚未明确，这一点很重要，因为细胞外组蛋白对内皮细胞和气道上皮细胞具有细胞毒性。目的：探讨细胞外组蛋白在COPD疾病进展中的作用。方法：我们分析了有和没有疾病的戒烟者的肺核蛋白质组学。还对H3.3的后果进行了进一步的研究。测量和主要结果：一个惊人的发现是copd特异性高乙酰化组蛋白H3.3增加了8倍。高乙酰化使H3.3抵抗蛋白酶体降解，尽管泛素化；当与COPD中已知的蛋白酶体活性降低相结合时，这种抵抗有助于解释H3.3水平升高的原因。使用抗h3抗体，我们在COPD样本的气道管腔、肺泡液和血浆中发现H3.3。H3.3对肺结构细胞具有细胞毒性，其机制涉及Ca2+稳态的扰动和线粒体毒性。我们使用原代人气道上皮细胞，发现H3的C或N端抗体可以部分逆转H3.3的毒性。结论：我们的数据表明存在一个不受控制的正反馈循环，受损细胞释放乙酰化的H3.3，导致更多的损伤，增加H3.3的释放，并促进疾病的进展。
Rationale: Shifts in the gene expression of nuclear protein in chronic obstructive pulmonary disease (COPD), a progressive disease that is characterized by extensive lung inflammation and apoptosis, are common; however, the extent of the elevation of the core histones, which are the major components of nuclear proteins and their consequences in COPD, has not been characterized, which is important because extracellular histones are cytotoxic to endothelial and airway epithelial cells.Objectives: To investigate the role of extracellular histones in COPD disease progression.Methods: We analyzed the nuclear lung proteomes of ex-smokers with and without the disease. Further studies on the consequences of H3.3 were also performed.Measurements and Main Results: A striking finding was a COPD-specific eightfold increase of hyperacetylated histone H3.3. The hyperacetylation renders H3.3 resistant to proteasomal degradation despite ubiquitination; when combined with the reduction in proteasome activity that is known for COPD, this resistance helps account for the increased levels of H3.3. Using anti-H3 antibodies, we found H3.3 in the airway lumen, alveolar fluid, and plasma of COPD samples. H3.3 was cytotoxic to lung structural cells via a mechanism that involves the perturbation of Ca2+ homeostasis and mitochondrial toxicity. We used the primary human airway epithelial cells and found that the antibodies to either the C or N terminus of H3 could partially reverse H3.3 toxicity.Conclusions: Our data indicate that there is an uncontrolled positive feedback loop in which the damaged cells release acetylated H3.3, which causes more damage, adds H3.3 release, and contributes toward the disease progression.