Metalloprotease meprin β is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding

Jäckle, Felix; Schmidt, Frederike; Wichert, Rielana; Arnold, Philipp; Prox, Johannes; Mangold, Martin; Ohler, Anke; Pietrzik, Claus U.; Koudelka, Tomas; Tholey, Andreas; Gütschow, Michael; Stirnberg, Marit; Becker‐Pauly, Christoph

doi:10.1042/bj20141417

Cited by 34 publications

(38 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Primary antibodies included rabbit-anti-CT-Ab (#SC661; Santa Cruz), rabbit-anti-actin (A2066, Sigma-Aldrich, Steinheim, Germany), rabbit-anti-GAPDH (14C10, Cell Signaling, Frankfurt am Main, Germany), rabbit-anti-meprin α (self-designed at Pineda, Berlin, Germany), and rabbit-anti-meprin β72, mouse-anti-human-IL-6R (4–11)73 and goat-anti-mouse-IL-6R (AF1830, R&D systems, Wiesbaden-Nordenstadt, Germany). Secondary antibodies used were Alexa Fluor 488, biotinylated antibodies (Molecular Probes, Eugene, USA) and peroxidase conjugated antibodies (Dianova, Hamburg, Germany).…”

Section: Methodsmentioning

confidence: 99%

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Arnold

Boll

Rothaug

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction.

show abstract

Section: Methodsmentioning

confidence: 99%

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Arnold

Boll

Rothaug

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Matriptase‐2 is a member of the type II transmembrane serine proteases (TTSPs), an understudied group of 17 membrane‐bound serine proteases (Szabo & Bugge, ), and has been reported to shed APP within the amyloid β domain, at least in transfected cells or in vitro (Beckmann et al , ). Other TTSPs appear to cleave predominantly soluble proteins or activate membrane‐bound proteins, but without shedding them in their juxtamembrane domains (Jackle et al , ; Murray et al , ). Thus, at present TTSPs belong to the group of “part‐time” sheddases.…”

Section: Hardware: Canonical Sheddasesmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

View full text Add to dashboard Cite

Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

show abstract

“…Indeed, not even trypsin was able to cleave off the propeptide of full length meprin β, which led to the assumption that possible candidates are most likely membrane bound serine proteases. In this regard, matriptase-2 (MT-2), a type 2 transmembrane protein, was found to fully activate meprin β at the cell surface (Jäckle et al, 2015). Consequently, MT-2 mediated activation of meprin β resulted in increased APP shedding and subsequently decreased sAPPα levels.…”

Section: Activationmentioning

confidence: 99%

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

Becker‐Pauly

Pietrzik

2017

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid hypothesis of Alzheimer's disease, promoting neurodegeneration. The N-terminal 11 kDa and 20 kDa peptide fragments represent physiological cleavage products, since they are found in human brains under different diseased or non-diseased states, whereas these fragments are completely missing in brains of meprin β knock-out animals. Meprin β is not only a sheddase of adhesion molecules, such as APP, but was additionally demonstrated to cleave within the prodomain of ADAM10. Activated ADAM10, the α-secretase of APP, is then able to shed meprin β from the cell surface thereby abolishing the β-secretase activity. All together meprin β seems to be a novel player in APP processing events, even influencing other enzymes involved in APP cleavage.

show abstract

Metalloprotease meprin β is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding

Cited by 34 publications

References 37 publications

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

Contact Info

Product

Resources

About