Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

A Schütte, A Ermund, C Becker-Pauly… - Proceedings of the …, 2014 - National Acad Sciences
A Schütte, A Ermund, C Becker-Pauly, MEV Johansson, AM Rodriguez-Pineiro, F Bäckhed…
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
The mucus that covers and protects the epithelium of the intestine is built around its major
structural component, the gel-forming MUC2 mucin. The gel-forming mucins have
traditionally been assumed to be secreted as nonattached. The colon has a two-layered
mucus system where the inner mucus is attached to the epithelium, whereas the small
intestine normally has a nonattached mucus. However, the mucus of the small intestine of
meprin β-deficient mice was now found to be attached. Meprin β is an endogenous zinc …
The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a two-layered mucus system where the inner mucus is attached to the epithelium, whereas the small intestine normally has a nonattached mucus. However, the mucus of the small intestine of meprin β-deficient mice was now found to be attached. Meprin β is an endogenous zinc-dependent metalloprotease now shown to cleave the N-terminal region of the MUC2 mucin at two specific sites. When recombinant meprin β was added to the attached mucus of meprin β-deficient mice, the mucus was detached from the epithelium. Similar to meprin β-deficient mice, germ-free mice have attached mucus as they did not shed the membrane-anchored meprin β into the luminal mucus. The ileal mucus of cystic fibrosis (CF) mice with a nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channel was recently shown to be attached to the epithelium. Addition of recombinant meprin β to CF mucus did not release the mucus, but further addition of bicarbonate rendered the CF mucus normal, suggesting that MUC2 unfolding exposed the meprin β cleavage sites. Mucus is thus secreted attached to the goblet cells and requires an enzyme, meprin β in the small intestine, to be detached and released into the intestinal lumen. This process regulates mucus properties, can be triggered by bacterial contact, and is nonfunctional in CF due to poor mucin unfolding.
National Acad Sciences