ADAM10 sheddase activation is controlled by cell membrane asymmetry

Bleibaum, Florian; Sommer, Anselm; Veit, Martin; Rabe, Björn; Andrä, Jörg; Kunzelmann, Karl; Nehls, Christian; Correa, Wilmar; Gutsmann, Thomas; Grötzinger, Joachim; Bhakdi, Sucharit; Reiß, Karina

doi:10.1093/jmcb/mjz008

Cited by 54 publications

(84 citation statements)

References 51 publications

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“…The requirement of a membrane-bound form for ADAM10 activity was further highly supported by ndings of a study showing that only the active form of this metalloproteinase is expressed at the surface of different cell types, including leukocytes derived from peripheral blood (30). Moreover, the negatively charged phospholipid phosphatidylserine (PS) translocation to the outer membrane lea et is pivotal for ADAM10 to exert its sheddase function (31).…”

Section: Discussionmentioning

confidence: 96%

ADAM10 plasma levels predict worsening in cognition of older adults: a 3-year follow-up study

Monteiro

Oliveira

Manzine

et al. 2020

Preprint

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Background: Blood-based biomarkers for Alzheimer’s disease (AD) are highly needed in clinic practice. So far, the gold standards for AD diagnosis are brain neuroimaging and beta-amyloid peptide, total tau and phosphorylated tau in cerebrospinal fluid (CSF), however, they are not attractive for large-scale screening. Blood-based biomarkers will allow an initial large-scale screening of patients under suspicion that could later be tested for the already established CSF biomarkers. To this regard, we and other research groups have already described that the plasma and platelet levels of ADAM10 are higher or lower, respectively, in patients with AD, compared to those cognitively healthy. Methods: This was a three-year longitudinal cohort study that included 219 community-dwelling older adults. Sociodemographic, clinical, lifestyle, depressive symptoms (GDS) and cognitive data (Mini-Mental State Examination, MMSE; Clock Drawing test, CDT) were gathered. The measurement of ADAM10 plasma levels was performed using a sandwich ELISA kit. Bivariate comparisons between groups were performed using Wilcoxon-Mann-Whitney for continuous data and Pearson’s chi-square tests with Yates continuity correction, for categorical data. Longitudinal analyzes of changes in the MMSE score were performed using Linear Mixed-Effects modeling.Results: Baseline MMSE score and ADAM10 values were significantly associated with MMSE score values on the follow-up assessment. When analyzing the interaction with time, having a normal MMSE at baseline and ADAM10 plasma levels presented a significant and independent negative association with MMSE score values on the follow-up assessment. The analyses also showed that the effect of ADAM10 plasma levels on decreasing MMSE score values on follow-up seems to be more pronounced in those with normal MMSE at baseline. Taken together, these results provide the first direct evidence that changes in ADAM10 plasma levels are predictors of cognitive worsening in older adults.Conclusions: Considering that ADAM10 increase in plasma is detected as soon as in mild cognitive impairment (MCI) patients, the results presented here may support the complementary clinical use of this biomarker, in addition to the classical AD biomarkers. Moreover, this work can shed light on the study of blood biomarkers for AD and contribute to the advancement of the area.

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Section: Discussionmentioning

confidence: 96%

ADAM10 plasma levels predict worsening in cognition of older adults: a 3-year follow-up study

Monteiro

Oliveira

Manzine

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The requirement of a membrane-bound form for ADAM10 activity was further highly supported by ndings of a study showing that only the active form of this metalloproteinase is expressed at the surface of different cell types, including leukocytes derived from peripheral blood [29]. Moreover, the negatively charged phospholipid phosphatidylserine (PS) translocation to the outer membrane lea et is pivotal for ADAM10 to exert its sheddase function [30].…”

Section: Discussionmentioning

confidence: 96%

ADAM10 Plasma Levels Predict Worsening in Cognition of Older Adults: A 3-Year Follow-Up Study

Monteiro

Oliveira

Manzine

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Blood-based biomarkers for Alzheimer’s disease (AD) are highly needed in clinic practice. So far, the gold standards for AD diagnosis are brain neuroimaging and beta-amyloid peptide, total tau and phosphorylated tau in cerebrospinal fluid (CSF), however, they are not attractive for large-scale screening. Blood-based biomarkers will allow an initial large-scale screening of patients under suspicion that could later be tested for the already established CSF biomarkers. To this regard, we and other research groups have already described that the plasma and platelet levels of ADAM10 are higher or lower, respectively, in patients with AD, compared to those cognitively healthy. Methods This was a three-year longitudinal cohort study that included 219 community-dwelling older adults. Sociodemographic, clinical, lifestyle, depressive symptoms (GDS) and cognitive data (Mini-Mental State Examination, MMSE; Clock Drawing test, CDT) were gathered. The measurement of ADAM10 plasma levels was performed using a sandwich ELISA kit. Bivariate comparisons between groups were performed using Wilcoxon-Mann-Whitney for continuous data and Pearson’s chi-square tests with Yates continuity correction, for categorical data. Longitudinal analyzes of changes in the MMSE score were performed using Linear Mixed-Effects modeling. Results Baseline MMSE score and ADAM10 values were significantly associated with MMSE score values on the follow-up assessment. When analyzing the interaction with time, having a normal MMSE at baseline and ADAM10 plasma levels presented a significant and independent negative association with MMSE score values on the follow-up assessment. The analyses also showed that the effect of ADAM10 plasma levels on decreasing MMSE score values on follow-up seems to be more pronounced in those with normal MMSE at baseline. Taken together, these results provide the first direct evidence that changes in ADAM10 plasma levels are predictors of cognitive worsening in older adults. Conclusions Considering that ADAM10 increase in plasma is detected as soon as in mild cognitive impairment (MCI) patients, the results presented here may support the complementary clinical use of this biomarker, in addition to the classical AD biomarkers. Moreover, this work can shed light on the study of blood biomarkers for AD and contribute to the advancement of the area.

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“…The precise mechanism by which Map evokes ADAM10 activation through mitochondrial targeting is still not well understood. Recent studies have shown that membrane externalized phosphatidylserine is required for activating the ADAM10 sheddase activity ( 62 ). Hence, an interesting hypothesis would be that the induction of mitochondrial cell death by Map is caused by phosphatidylserine externalization.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Targeting of the Enteropathogenic Escherichia coli Map Triggers Calcium Mobilization, ADAM10-MAP Kinase Signaling, and Host Cell Apoptosis

Ramachandran

Spiegel

Keren

et al. 2020

mBio

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The ability of diarrheagenic bacterial pathogens, such as enteropathogenic Escherichia coli (EPEC), to modulate the activity of mitogen-activated protein kinases (MAPKs) and cell survival has been suggested to benefit bacterial colonization and infection. However, our understanding of the mechanisms by which EPEC modulate these functions is incomplete. In this study, we show that the EPEC type III secreted effector Map stimulates the sheddase activity of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and the ERK and p38 MAPK signaling cascades. Remarkably, all these activities were dependent upon the ability of Map to target host mitochondria, mainly via its mitochondrial toxicity region (MTR). Map targeting of mitochondria disrupted the mitochondrial membrane potential, causing extrusion of mitochondrial Ca2+ into the host cell cytoplasm. We also found that Map targeting of mitochondria is essential for triggering host cell apoptosis. Based on these findings, we propose a model whereby Map imported into mitochondria causes mitochondrial dysfunction and Ca2+ efflux into the host cytoplasm. Since Ca2+ has been reported to promote ADAM10 activation, the acute elevation of Ca2+ in the cytoplasm may stimulate the ADAM10 sheddase activity, resulting in the release of epidermal growth factors that stimulate the ERK signaling cascade. As p38 activity is also Ca2+ sensitive, elevation in cytoplasmic Ca2+ may independently also activate p38. We hypothesize that Map-dependent MAPK activation, combined with Map-mediated mitochondrial dysfunction, evokes mitochondrial host cell apoptosis, potentially contributing to EPEC colonization and infection of the gut. IMPORTANCE Enteropathogenic E. coli (EPEC) is an important human diarrhea-causing bacterium. The pathogenic effects of EPEC largely depend upon its ability to inject a series of proteins, termed effectors, into the host cells. One such effector is the mitochondrion-associated protein (Map). Map has been shown to induce actin-rich projections (i.e., filopodia) on the infected cell surface and activate a Rho GTPase enzyme termed Cdc42. Nonetheless, although most injected Map localizes to host mitochondria, its functions in the mitochondria remain unknown. Here, we show that Map targeting of mitochondria stimulates the disruption of mitochondrial membrane potential to induce Ca2+ efflux into the host cytoplasm. The efflux stimulates the activity of a protein termed ADAM10, which induces activation of a mitogen-activated protein kinase cascade leading to host cell apoptosis. As apoptosis plays a central role in host-pathogen interactions, our findings provide novel insights into the functions of mitochondrial Map in promoting the EPEC disease.

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ADAM10 sheddase activation is controlled by cell membrane asymmetry

Cited by 54 publications

References 51 publications

ADAM10 plasma levels predict worsening in cognition of older adults: a 3-year follow-up study

ADAM10 plasma levels predict worsening in cognition of older adults: a 3-year follow-up study

ADAM10 Plasma Levels Predict Worsening in Cognition of Older Adults: A 3-Year Follow-Up Study

Mitochondrial Targeting of the Enteropathogenic Escherichia coli Map Triggers Calcium Mobilization, ADAM10-MAP Kinase Signaling, and Host Cell Apoptosis

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