Calcium-activated Chloride Channel Regulator 1 (CLCA1) Controls Mucus Expansion in Colon by Proteolytic Activity

Many epithelial surfaces of the body are covered with protective mucus, and disrupted mucus homeostasis is coupled to diseases such as ulcerative colitis, helminth infection, cystic fibrosis, and chronic obstructive lung disease. However, little is known how a balanced mucus system is maintained. By investigating the involvement of proteases in colonic mucus dynamics we identified metalloprotease activity to be a key contributor to mucus expansion. The effect was mediated by calcium-activated chloride channel regulator 1 (CLCA1) as application of recombinant CLCA1 on intestinal mucus in freshly dissected tissue resulted in increased mucus thickness independently of ion and mucus secretion, but dependent on its metallohydrolase activity. Further, CLCA1 modulated mucus dynamics in both human and mouse, and knock-out of CLCA1 in mice was compensated for by cysteine proteases. Our results suggest that CLCA1 is involved in intestinal mucus homeostasis by facilitating processing and removal of mucus to prevent stagnation. In light of our findings, we suggest future studies to investigate if upregulation of CLCA1 in diseases associated with mucus accumulation could facilitate removal of mucus in an attempt to maintain homeostasis.
Graphical Abstract Unlabelled Image
Highlights • Endogenous metalloprotease activity is important for intestinal mucus dynamics. • CLCA1 acts as a metalloprotease in intestinal mucus and this function is independent of ion and mucus secretion. • CLCA1 is involved in the transition from the inner to outer mucus layer in colon. In this article we provide evidence that endogenous enzyme activity is important for normal processing of the intestinal mucus layer, which creates a protective barrier against the vast number of bacteria in the large intestine. CLCA1, a highly abundant intestinal mucus protein, seems to be a key contributor to mucus processing. This role for CLCA1 is different from what was previously described. As mucus clearance is of importance for several diseases, better understanding of mucus processing could be of great importance to develop new therapies.