Role of TRIM-16-mediated lysophagy in COPD pathogenesis

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<b>Introduction:</b> Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes, and galectin-3 and tripartite motif proteins (TRIM)16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome selective autophagy for maintaining lysosome function. <b>Methods:</b> To examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis, using human bronchial epithelial cells (HBEC) and lung tissues. <b>Results:</b> CS extract (CSE) induced LMP as detected by galectin-3 accumulation and TRIM16 was involved in CSE-induced lysophagy. Impaired lysophagy was associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed increase in lipofuscin, aggresome, and galectin-3 puncta reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. HBEC isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. <b>Conclusion:</b> Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.