Role of lamin B1 in COPD pathogenesis

Introduction: Downregulation of lamin B1 has been recognized to be a crucial step for development of full senescence. Accelerated cellular senescence linked to dysregulated autophagy and mTOR activation have been implicated in COPD pathogenesis. We have demonstrated reduced lamin B1 was associated with COPD pathogenesis through activating mTOR during cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). Methods: To further elucidate the mechanisms for lamin B1 downregulation related to autophagy, confocal microscopic evaluation and immunoprecipitation were performed in HBEC. DNA microarray and mass spectrometry were examined. C57BL/6J mice were exposed to cigarette smoke over a 6-month period as COPD model. Results: LaminB1 reduction during CSE exposure was recovered by lysosomal protease inhibitors and ATG5 knockdown. Confocal microscopic evaluation detected cytoplasmic colocarization between lamin B1 and LC3, reflecting autophagic degradation. DNA microarray and mass spectrometry demonstrated decrease in DEPTOR expression, an mTOR inhibitor by lamin B1 knockdown, which was responsible for subsequent autophagy impairment and cellular senescence. Lamin B1 knockdown also enhanced histone modification of H4K20me3. Decreased lamin B1 and DEPTOR with concomitantly increased p62 reflecting insufficient autophagic degradation were demonstrated in lung homogenate from cigarette smoke exposed-mice. Conclusion: These findings suggest CSE-induced autophagic degradation is involved in the mechanisms of lamin B1 reduction. Phenotypic alterations linked to cellular senescence can be attributed to epigenetic histone modifications by reduced laminB1.