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Ectodomain Shedding: Current Trends and Challenges to Investigate Functions of Sheddases

A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membrane Functions".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 12386

Special Issue Editors

Dr. Simone Dario Scilabra

E-Mail Website
Guest Editor
Proteomics group of Fondazione Ri.MED, Department of Research IRCCS ISMETT, via Ernesto Tricomi 5, 90145 Palermo, Italy
Interests: metalloproteinases; iRhoms; proteomics; arthritis
Dr. Aldo Nicosia

E-Mail Website
Guest Editor
1. Institute for Biomedical Research and Innovation-National Research Council (IRIB-CNR), 90146 Palermo, Italy
2. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy
Interests: theranostics; biomaterials; cancer targeted therapies; regenerative medicine; pathway-focused gene expression analyses; biomedical applications
Special Issues, Collections and Topics in MDPI journals
Dr. Jasenka Rudan Njavro

E-Mail Website
Guest Editor
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Interests: ectodomain shedding; BACE secretases; immunotherapy; microglial function; Alzheimer's disease
Dr. Stephan A. Mueller

E-Mail Website
Guest Editor
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Strasse 17, 81377 Munich, Germany
Interests: proteomics; proteases; ectodomain shedding

Special Issue Information

Dear Colleagues,

About 25% of the coded proteins in the human genome are transmembrane proteins. The proteolytic release of transmembrane proteins, the so-called “ectodomain shedding”, is a key mechanism in several biological processes, including cell-to-cell communication, cell adhesion, and transport. Members of several different families of membrane-bound proteases have been shown to act as sheddases, including a disintegrin and metalloproteases (ADAMs), BACE proteases, and membrane-type metalloproteinases (MT-MMPs). Recently, a much broader range of proteases, including intramembrane and soluble proteases, have been found to cleave transmembrane proteins. Given their fundamental role in cell biology, the activity of sheddases must be finely modulated. Aberrant shedding, as well as its abnormal inhibition, lead to pathological conditions, including cancer and arthritis. Thus, sheddases have been widely investigated as potential drug targets in recent years.

This Special Issue of Membranes aims to provide novel insights into the physiological and pathological functions of sheddases. It aims to collect research articles and critical reviews that will contribute to dissect functions of protein ectodomain shedding in health and disease and increase our current understanding of sheddases and their substrates. Special attention will be paid to novel approaches to investigate the activity and functions of sheddases and their inhibitors, such as the proteomic profiling of sheddase substrates.

Dr. Simone Scilabra
Dr. Aldo Nicosia
Dr. Jasenka Rudan Njavro
Dr. Stephan A. Mueller
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Membranes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ectodomain shedding
  • Sheddases
  • ADAMs
  • BACE secretases
  • Matrix metalloproteases
  • Substrate identification
  • Proteomics
  • Therapeutic target

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Published Papers (4 papers)

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Research

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13 pages, 2239 KiB  
Article
Quantitative Proteomics Reveals That ADAM15 Can Have Proteolytic-Independent Functions in the Steady State
by Chun-Yao Yang, Simone Bonelli, Matteo Calligaris, Anna Paola Carreca, Stephan A. Müller, Stefan F. Lichtenthaler, Linda Troeberg and Simone D. Scilabra
Membranes 2022, 12(6), 578; https://doi.org/10.3390/membranes12060578 - 31 May 2022
Cited by 2 | Viewed by 2090
Abstract
A disintegrin and metalloproteinase 15 (ADAM15) is a member of the ADAM family of sheddases. Its genetic ablation in mice suggests that ADAM15 plays an important role in a wide variety of biological functions, including cartilage homeostasis. Nevertheless, while the substrate repertoire of [...] Read more.
A disintegrin and metalloproteinase 15 (ADAM15) is a member of the ADAM family of sheddases. Its genetic ablation in mice suggests that ADAM15 plays an important role in a wide variety of biological functions, including cartilage homeostasis. Nevertheless, while the substrate repertoire of other members of the ADAM family, including ADAM10 and ADAM17, is largely established, little is known about the substrates of ADAM15 and how it exerts its biological functions. Herein, we used unbiased proteomics to identify ADAM15 substrates and proteins regulated by the proteinase in chondrocyte-like HTB94 cells. ADAM15 silencing did not induce major changes in the secretome composition of HTB94 cells, as revealed by two different proteomic approaches. Conversely, overexpression of ADAM15 remodeled the secretome, with levels of several secreted proteins being altered compared to GFP-overexpressing controls. However, the analysis did not identify potential substrates of the sheddase, i.e., transmembrane proteins released by ADAM15 in the extracellular milieu. Intriguingly, secretome analysis and immunoblotting demonstrated that ADAM15 overexpression increased secreted levels of tissue inhibitor of metalloproteinases 3 (TIMP-3), a major regulator of extracellular matrix turnover. An inactive form of ADAM15 led to a similar increase in the inhibitor, indicating that ADAM15 regulates TIMP-3 secretion by an unknown mechanism independent of its catalytic activity. In conclusion, high-resolution quantitative proteomics of HTB94 cells manipulated to have increased or decreased ADAM15 expression did not identify canonical substrates of the proteinase in the steady state, but it revealed that ADAM15 can modulate the secretome in a catalytically-independent manner. Full article
(This article belongs to the Special Issue Ectodomain Shedding: Current Trends and Challenges to Investigate Functions of Sheddases)
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15 pages, 1791 KiB  
Article
Influence of Anoctamin-4 and -9 on ADAM10 and ADAM17 Sheddase Function
by Sinje Leitzke, Jana Seidel, Björn Ahrens, Rainer Schreiber, Karl Kunzelmann, Maria Sperrhacke, Sucharit Bhakdi and Karina Reiss
Membranes 2022, 12(2), 123; https://doi.org/10.3390/membranes12020123 - 20 Jan 2022
Cited by 7 | Viewed by 2951
Abstract
Ca2+-activated Cl− channels (TMEM16, also known as anoctamins) perform important functions in cell physiology, including modulation of cell proliferation and cancer growth. Many members, including TMEM16F/ANO6, additionally act as Ca2+-activated phospholipid scramblases. We recently presented evidence that ANO6-dependent [...] Read more.
Ca2+-activated Cl− channels (TMEM16, also known as anoctamins) perform important functions in cell physiology, including modulation of cell proliferation and cancer growth. Many members, including TMEM16F/ANO6, additionally act as Ca2+-activated phospholipid scramblases. We recently presented evidence that ANO6-dependent surface exposure of phosphatidylserine (PS) is pivotal for the disintegrin-like metalloproteases ADAM10 and ADAM17 to exert their sheddase function. Here, we compared the influence of seven ANO family members (ANO1, 4, 5, 6, 7, 9, and 10) on ADAM sheddase activity. Similar to ANO6, overexpression of ANO4 and ANO9 led to increased release of ADAM10 and ADAM17 substrates, such as betacellulin, TGFα, and amphiregulin (AREG), upon ionophore stimulation in HEK cells. Inhibitor experiments indicated that ANO4/ANO9-mediated enhancement of TGFα-cleavage broadened the spectrum of participating metalloproteinases. Annexin V-staining demonstrated increased externalisation of PS in ANO4/ANO9-overexpressing cells. Competition experiments with the soluble PS-headgroup phosphorylserine indicated that the ANO4/ANO9 effects were due to increased PS exposure. Overexpression of ANO4 or ANO9 in human cervical cancer cells (HeLa), enhanced constitutive shedding of the growth factor AREG and increased cell proliferation. We conclude that ANO4 and ANO9, by virtue of their scramblase activity, may play a role as important regulators of ADAM-dependent cellular functions. Full article
(This article belongs to the Special Issue Ectodomain Shedding: Current Trends and Challenges to Investigate Functions of Sheddases)
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Review

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13 pages, 1305 KiB  
Review
Scramblases as Regulators of Proteolytic ADAM Function
by Karina Reiss, Sinje Leitzke, Jana Seidel, Maria Sperrhacke and Sucharit Bhakdi
Membranes 2022, 12(2), 185; https://doi.org/10.3390/membranes12020185 - 4 Feb 2022
Cited by 10 | Viewed by 2820
Abstract
Proteolytic ectodomain release is a key mechanism for regulating the function of many cell surface proteins. The sheddases ADAM10 and ADAM17 are the best-characterized members of the family of transmembrane disintegrin-like metalloproteinase. Constitutive proteolytic activities are low but can be abruptly upregulated via [...] Read more.
Proteolytic ectodomain release is a key mechanism for regulating the function of many cell surface proteins. The sheddases ADAM10 and ADAM17 are the best-characterized members of the family of transmembrane disintegrin-like metalloproteinase. Constitutive proteolytic activities are low but can be abruptly upregulated via inside-out signaling triggered by diverse activating events. Emerging evidence indicates that the plasma membrane itself must be assigned a dominant role in upregulation of sheddase function. Data are discussed that tentatively identify phospholipid scramblases as central players during these events. We propose that scramblase-dependent externalization of the negatively charged phospholipid phosphatidylserine (PS) plays an important role in the final activation step of ADAM10 and ADAM17. In this manuscript, we summarize the current knowledge on the interplay of cell membrane changes, PS exposure, and proteolytic activity of transmembrane proteases as well as the potential consequences in the context of immune response, infection, and cancer. The novel concept that scramblases regulate the action of ADAM-proteases may be extendable to other functional proteins that act at the cell surface. Full article
(This article belongs to the Special Issue Ectodomain Shedding: Current Trends and Challenges to Investigate Functions of Sheddases)
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9 pages, 619 KiB  
Review
Secretases Related to Amyloid Precursor Protein Processing
by Xiaoling Liu, Yan Liu and Shangrong Ji
Membranes 2021, 11(12), 983; https://doi.org/10.3390/membranes11120983 - 15 Dec 2021
Cited by 16 | Viewed by 3205
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce β-amyloid protein (Aβ), are a major pathological feature of AD. In recent years, a large number of studies have been conducted on the APP processing pathways and the role of secretion. This paper provides a summary of the involvement of secretases in the processing of APP and the potential drug targets that could provide new directions for AD therapy. Full article
(This article belongs to the Special Issue Ectodomain Shedding: Current Trends and Challenges to Investigate Functions of Sheddases)
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