Posttranslational regulation of the metalloprotease meprin β

Malfunction of proteases can lead to severe pathologies and dysregulation of meprin β is associated with inflammation, fibrosis, neurodegeneration and tumorigenesis. Interestingly, MT1-MMP as well as ADAM10 and ADAM17 are also associated with these diseases. Moreover, meprin β, MT1-MMP and ADAM10/17 even share a partly combined substrate pool including the interleukin receptors (IL-R) IL-6R and IL-11R and the amyloid precursor protein (APP).

The first part of this thesis revealed a direct mutual shedding between MT1-MMP and meprin β and showed a remarkable overlap of shedding properties of MT1-MMP and ADAM10/17 with regard to meprin β. Thus, membrane-bound MT1-MMP was only able to shed the inactive human zymogen pro-meprin β, but not murine meprin β, similar to ADAM10/17. Furthermore, MT1-MMP and ADAM10/17 even used the same cleavage site within human meprin β, localized between Pro602 and Ser603.

The second part of this thesis demonstrated that glycosylations are also an important regulatory mechanism for the shedding of meprin β. Herein, O-glycosylations at position Thr604 in murine meprin β and at position Thr599 in human meprin β were validated, as well as at position Thr601 for the cancer-associated human meprin β variant A601T. The O-glycosylation at Thr604 protected murine meprin β from its shedding in vitro. A similar function was observed for glycosylated Thr601 in the cancer-associated human meprin β variant. On the contrary, deletions of O- and N-glycosylation sites within the cleavage region of meprin β increased its own ectodomain shedding, but also hindered the shedding capability of human meprin β with regard to IL-6R, thereby reducing IL-6 trans-signaling.


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