Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease
Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease
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DOI：
10.1073/pnas.2019167118
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发表时间：
2021-06-29
影响因子：
11.1
通讯作者：
Satoh, Takashi
中科院分区：
文献类型：
--
作者：
Kawasaki, Takahiro;Sugihara, Fuminori;Satoh, Takashi
慢性阻塞性肺疾病（COPD/肺气肿）是一种危及生命的疾病，几乎没有有效的治疗方法。吸烟引起的氧化应激、气道炎症和肺细胞凋亡参与了COPD/肺气肿的发病机制并导致肺泡间隔破坏。在这里，我们表明，FCH和双SH 3域1（FCHSD 1）的表达水平显着增加，在响应弹性蛋白酶滴注，COPD的实验模型小鼠。FCHSD 1是具有两个SH 3结构域的F-BAR家族的成员。我们发现，Fchsd 1基因敲除（Fchsd 1（-/-））小鼠对弹性蛋白酶诱导的空域扩大的保护。与WT小鼠相比，Fchsd 1（-/-）小鼠的弹性蛋白酶灌注肺显示炎症和肺水肿减轻。我们还发现，弹性蛋白酶诱导的Sirtuin 1（SIRT 1）水平降低，一种组蛋白脱乙酰酶，据报道可防止肺气肿，在Fchsd 1（-/-）小鼠的肺中减弱。此外，FCHSD 1缺陷增强核因子样2（NRF 2），氧化还原敏感的转录因子，核转位后，过氧化氢刺激。相反，Fchsd 1过表达抑制NRF 2核转位，并增加SIRT 1水平的下降。值得注意的是，FCHSD 1与NRF 2和SNX 9相互作用。我们的研究结果表明，FCHSD 1与NRF 2和SNX 9在胞质溶胶中形成多复合物，阻止NRF 2易位到细胞核。我们认为FCHSD 1通过抑制NRF 2的核转位，从而导致SIRT 1的下调，从而促进肺气肿的发生发展。
Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cig-arette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal de-struction. Here we show that the expression level of FCH and dou-ble SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that Fchsd1 knockout (Fchsd1(-/-)) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of Fchsd1(-/-) mice showed reduced inflammation and apopto-sis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of Fchsd1(-/-) mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), a redox-sensitive tran-scription factor, following H2O2 stimulation. Conversely, Fchsd1 over-expression inhibited NRF2 nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of em-physema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.