The intestinal role of meprin metalloproteases

The metalloproteases meprin α and meprin β 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 α and meprin β form covalently linked heterodimers tethering meprin α 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 α/β heterodimers. Interestingly, galectin‑3 deficient and meprin α/β double knockout mice show similar alterations in their microbiome in comparison to wildtype mice. We further demonstrate that meprin α/β 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 α/β heterodimers may play a key role in colon host-microbiome homeostasis.


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