Proteolytic processing of galectin-3 by meprin metalloproteases is crucial for host-microbiome homeostasis

The metalloproteases meprin alpha and meprin beta are highly expressed in the healthy gut but significantly decreased in inflammatory bowel disease, implicating a protective role in mucosal homeostasis. In the colon, meprin alpha and meprin beta form covalently linked heterodimers tethering meprin alpha to the plasma membrane, therefore presenting dual proteolytic activity in a unique enzyme complex. To unravel its function, we applied N-terminomics and identified galectin-3 as the major intestinal substrate for meprin alpha/beta heterodimers. Galectin-3-deficient and meprin alpha/beta double knockout mice show similar alterations in their microbiome in comparison to wild-type mice. We further demonstrate that meprin alpha/beta heterodimers differentially process galectin-3 upon bacterial infection, in germ-free, conventionally housed (specific pathogen-free), or wildling mice, which in turn regulates the bacterial agglutination properties of galectin-3. Thus, the constitutive cleavage of galectin-3 by meprin alpha/beta heterodimers may play a key role in colon host-microbiome homeostasis.