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

Authors:

Cynthia Bülck, Elisabeth E L Nyström, Tomas Koudelka, Michael Mannbar-Frahm, Gerrit Andresen, Mariem Radhouani, Florian Tran, Franka Scharfenberg, Friederike Schrell, Fred Armbrust, Eileen Dahlke, Bei Zhao, Alex Vervaeke, Franziska Theilig, Philip Rosenstiel, Philipp Starkl, Stephan P Rosshart, Helmut Fickenscher, Andreas Tholey, Gunnar C Hansson, Christoph Becker-Pauly

Keywords:

Gastrointestinal Tract, Host-Microbiome interaction

Abstract:

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. Galectin-3-deficient and meprin α/β double knockout mice show similar alterations in their microbiome in comparison to wild-type 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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