Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease

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.