Mucin granules are degraded in the autophagosome-lysosome pathway as a means of resolving airway mucous cell metaplasia

Abstract

Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous cell metaplasia (MCM). The molecular pathways triggering MCM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagosome-lysosome pathway is required for resolution of MCM by degrading cytoplasmic mucins. We found increased intracellular levels of Muc5ac and Muc5b in autophagy-deficient mice. This difference was not due to defective mucin secretion. Instead, we found that Lamp1-labeled lysosomes surrounded mucin granules of mucous cells indicating that granules were being degraded. Using a model of resolution of mucous cell metaplasia in mice, we found increased lysosomal proteolytic activity that peaked in the days after inflammation. Autophagy-deficient mice had persistent accumulation of mucin granules that failed to decline due to reduced mucin degradation. We applied these findings in vitro to human airway epithelial cells (AECs). Activation of autophagy by mTOR inhibition led to degradation of mucin granules in AECs. Our findings indicate that during peak and resolution phases of MCM, mucin granules can be degraded by autophagy. The addition of mucin degradation to the existing paradigm of production and secretion may more fully explain how the secretory cells handle excess amounts of cytoplasmic mucin and offers a therapeutic target to speed resolution of MCM in airway disease exacerbations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/130534v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@94239org.highwire.dtl.DTLVardef@1dac6dforg.highwire.dtl.DTLVardef@368161org.highwire.dtl.DTLVardef@680b7d_HPS_FORMAT_FIGEXP M_FIG C_FIG