Meprin Metalloprotease Biology in Inflammation and Cancer

Meprin metalloproteases, comprising the paralogues meprin α and meprin β, are zinc-dependent enzymes predominantly expressed in epithelial tissues of the kidney and intestine but also found in leukocytes and various tumour cells. These proteases exist as secreted oligomers or membrane-anchored dimers and exert wide-ranging effects on the extracellular environment by cleaving matrix components, cytokines and growth factors. In homeostasis, meprins contribute to tissue repair, immune defence and extracellular matrix remodelling. However, dysregulated activity is implicated in acute and chronic inflammatory disorders, including inflammatory bowel disease and sepsis, as well as in tumour progression through enhanced invasion and metastatic dissemination. Meprin β mediates pro-inflammatory cytokine maturation, notably of interleukin-18, while both meprins generate soluble interleukin-6 receptor fragments to promote trans-signalling. In the tumour microenvironment, elevated meprin α contributes to cancer cell migration by degrading basement membranes and activating matrix metalloproteases. Structural diversity—ranging from giant secreted assemblies of meprin α to membrane-bound complexes of meprin β—underpins distinct substrate specificities and regulatory mechanisms such as ectodomain shedding. These multifaceted roles have prompted interest in selective inhibitors and probing of endogenous inhibitors, positioning meprins as targets for therapeutic intervention in inflammation and cancer.

Research from Nature Portfolio

High-resolution cryo-electron microscopy has elucidated the three-dimensional architecture of both zymogen and active forms of meprin α, revealing a colossal left-handed helical assembly of approximately 22 nm diameter. Oligomerisation enhances thermal and proteolytic stability without altering substrate specificity, and structural comparison with meprin β has identified unique active-site residues that may guide the design of selective inhibitors. Mammalian plasma fetuin-B has been shown to act as a potent and selective antagonist of astacin-family metalloproteases, including meprins, via a novel ‘raised-elephant-trunk’ mechanism. Tandem cystatin-like modules of fetuin-B insert into the active-site cleft, blocking the catalytic zinc ion while evading proteolytic cleavage, thus offering a blueprint for inhibitor development. Investigations into proteolytic processing of the interleukin-6 receptor have demonstrated that soluble meprin α and membrane-bound meprin β cleave the receptor at a distinct site from other sheddases, generating bioactive fragments that drive IL-6 trans-signalling; this unveils a regulatory axis between meprins and ADAM proteases in inflammatory cascades.

Meprin Metalloprotease Biology in Inflammation and Cancer publication trend

The graph below shows the total number of articles in meprin metalloprotease biology in inflammation and cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Metalloprotease: A protease that relies on a metal ion, usually zinc, in its active site to catalyse peptide bond hydrolysis.

Zymogen: An inactive enzyme precursor requiring proteolytic cleavage for activation.

Oligomerisation: The assembly of protein subunits into multi-unit complexes that modulate function and stability.

Ectodomain shedding: Proteolytic cleavage of the extracellular portion of a membrane protein, releasing a soluble fragment.

Trans-signalling: Cytokine signalling initiated by a soluble receptor–cytokine complex that activates cells lacking the membrane-bound receptor.

References

1. Synthesis and structure–activity relationships of pyrazole-based inhibitors of meprin α and β. Journal of Enzyme Inhibition and Medicinal Chemistry (2023).
2. Structural and evolutionary insights into astacin metallopeptidases. Frontiers in Molecular Biosciences (2023).
3. Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor. Nature Communications (2022).
4. Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling. Scientific Reports (2017).
5. Mammalian plasma fetuin-B is a selective inhibitor of ovastacin and meprin metalloproteinases. Scientific Reports (2019).
6. Prointerleukin-18 Is Activated by Meprin β in Vitro and in Vivo in Intestinal Inflammation*. Journal of Biological Chemistry (2008).
7. Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin. Oncotarget (2016).
8. Structure of Homo- and Hetero-oligomeric Meprin Metalloproteases DIMERS, TETRAMERS, AND HIGH MOLECULAR MASS MULTIMERS*. Journal of Biological Chemistry (2002).