The Cytoplasmic Domain of A Disintegrin and Metalloproteinase 10 (ADAM10) Regulates Its Constitutive Activity but Is Dispensable for Stimulated ADAM10-dependent Shedding

Maretzky, Thorsten; Evers, Astrid; Gall, Sylvie Le; Alabi, Rolake O.; Speck, Nancy A.; Reiß, Karina; Blobel, Carl P.

doi:10.1074/jbc.m114.603753

Cited by 36 publications

(37 citation statements)

References 41 publications

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“…Because ADAM17 and ADAM10 also do not require their ICDs for induced cleavage (30,(59)(60)(61), these findings suggest the existence of other regulatory proteins that could also receive ICD signaling input. As examples, inactive rhomboid proteins (iRhoms) (62) and annexins (63,64) interact with ADAM17 and/or substrates on the cell surface and regulate the cleavage of select ADAM17 substrates.…”

Section: Discussionmentioning

confidence: 93%

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Parra

Hartmann

Schubach

et al. 2015

Molecular and Cellular Biology

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bEctodomain cleavage by A-disintegrin and -metalloproteases (ADAMs) releases many important biologically active substrates and is therefore tightly controlled. Part of the regulation occurs on the level of the enzymes and affects their cell surface abundance and catalytic activity. ADAM-dependent proteolysis occurs outside the plasma membrane but is mostly controlled by intracellular signals. However, the intracellular domains (ICDs) of ADAM10 and -17 can be removed without consequences for induced cleavage, and so far it is unclear how intracellular signals address cleavage. We therefore explored whether substrates themselves could be chosen for proteolysis via ICD modification. We report here that CD44 (ADAM10 substrate), a receptor tyrosine kinase (RTK) coreceptor required for cellular migration, and pro-NRG1 (ADAM17 substrate), which releases the epidermal growth factor (EGF) ligand neuregulin required for axonal outgrowth and myelination, are indeed posttranslationally modified at their ICDs. Tetradecanoyl phorbol acetate (TPA)-induced CD44 cleavage requires dephosphorylation of ICD serine 291, while induced neuregulin release depends on the phosphorylation of several NRG1-ICD serines, in part mediated by protein kinase C␦ (PKC␦). Downregulation of PKC␦ inhibits neuregulin release and reduces ex vivo neurite outgrowth and myelination of trigeminal ganglion explants. Our results suggest that specific selection among numerous substrates of a given ADAM is determined by ICD modification of the substrate. Many transmembrane proteins on the cell surface are subject to proteolytic cleavage of their ectodomains, predominantly by metalloproteases (ectodomain shedding) (1-3). Ectodomain shedding regulates numerous important molecules involved in signal transfer between the extracellular space and the cell's interior and thus influences many cellular functions (1, 3). This includes, for example, the biological availability of epidermal growth factor (EGF) receptor ligands such as neuregulin (NRG1) (4, 5) and the modulation of complex cellular phenotypes required for contact inhibition of cells involving the hyaluronic acid receptor CD44 (4). NRG1 regulates neurite outgrowth and myelination but also has important functions in the development of other organs, for instance, the heart (6-9). When bound to hyaluronan, CD44 triggers a proliferation-inhibitory pathway (10-12). On the other hand, cancer stem cells carry CD44 (13-15), and, in this context, CD44 promotes tumor growth and metastasis (16-21), likely via alternative splice forms of CD44 that act as growth factor-enriching coreceptors for receptor tyrosine kinases (RTKs) (22,23).Inappropriate proteolysis of a number of shed substrates is associated with diseases when cleavage is either upregulated or reduced (24, 25). Equally, total knockout of substrates leads to significant phenotypes (26,27). This indicates that ectodomain cleavage requires tight regulation. How ectodomain cleavage is regulated and made substrate specific is largely unknown to date.The metallop...

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Section: Discussionmentioning

confidence: 93%

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Parra

Hartmann

Schubach

et al. 2015

Molecular and Cellular Biology

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“…For transient expression in MEFs, cells were transfected with plasmids encoding HA at a concentration of 500 ng/ml or 1,000 ng/ml or NA at 1,000 ng/ml using GenJet In Vitro DNA Transfection Reagent for MEFs (Ver. II) (SignaGen Laboratories) (48,49), according to the protocol recommended by the manufacturer. Briefly, the transfection complex was prepared at a ratio of GenJet to DNA of 3:1 (in microliters).…”

Section: Virus and Cellsmentioning

confidence: 99%

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Xia

Vijayan

Pritzl

et al. 2016

J Virol

114

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Influenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity. IMPORTANCE Influenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN Influenza virus infection causes seasonal and pandemic influenza with significant morbidity and mortality in humans (1). Outbreaks of avian influenza by highly pathogenic H5N1 and H7N9 viruses have raised the risk for the occurrence of another influenza pandemic (2-4). The genome of influenza A virus (IAV) encodes at least 11 proteins, including hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix proteins (M1 and M2), nonstructural proteins (NS1 and NS2), polymerase proteins (PA, PB1, and PB2), and PB1-F2 (5, 6). Antiviral drugs against influenza that block the function of viral proteins such as NA and M2 were developed to treat the infection. However, because of the high mutability, several strains of seasonal influenza and avian influenza viruses were shown to be resistant to the current antiviral drugs (6-8). Therefore, designing new therapeutics and identifying cellular targets of the infection are important to effectively control influenza.Type I interferons (IFNs), which include multiple IFN-␣ subtypes and IFN-␤, induce the expression of numerous interferonstimulated genes (ISGs) that establish antiviral states (9-11). Therefore, type I IFNs play an important role in the host defense system against viruses, including IAV (12)(13)(14). Influenza v...

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“…5b) (12). Given the membraneproximal site and rapid onset of proteolysis, we hypothesized that the membrane-bound ADAM protease family member was likely responsible for SIRP␣ shedding (14,15). The specific ADAM10 inhibitor GI254023X (GI) blocked LPS-stimulated shedding by ϳ60% at 0.1 M and completely blocked cleavage of SIRP␣ at 1 M (Fig.…”

Section: Sirp␣ Is Cleaved By a Matrix Metalloproteinase In Responsementioning

confidence: 99%

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

Londino

Gulick

Isenberg

et al. 2015

Journal of Biological Chemistry

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Signal regulatory protein ␣ (SIRP␣) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRP␣ ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-B signaling in macrophages. Here we observed that proteolysis of SIRP␣ during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. We mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRP␣ fragment by ␥-secretase was identified. Ectopic expression of a SIRP␣ mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-B pathway and suppressed STAT1 phosphorylation in response to TNF␣ to a greater extent than expression of wild-type SIRP␣. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRP␣ fragments in cells resulted in enhanced STAT-1 and NF-B pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and ␥-secretase on SIRP␣ cleavage promote inflammatory signaling.Inhibitory receptors including signal regulatory protein ␣ (SIRP␣), 2 CD33, SIGLECs (sialic acid-binding immunoglobulin-type lectins), CD66a, PD-1, CD31, PILRa (paired immunoglobin-like type 2 receptor ␣), CMRF35H, gp49B1, PECAM1, and others have been demonstrated to suppress the initiation of inflammatory signaling and contribute to the resolution of inflammation after infection (1, 2). SIRP␣ is membrane glycoprotein immunoreceptor that is expressed mainly in myeloid and neuronal cells (3). Ligation of SIRP␣ results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which recruit and activate SH2 domain-containing phosphotyrosine phosphatases SHP-1 and SHP-2 (4). SIRP␣ signaling results in reduced macrophage migration and phagocytosis and inhibition of NF-B signaling with reduction of release of NF-B-dependent cytokines in macrophages (5, 6). Phosphorylation of SIRP␣ ITIM domains also enhances JAK/STAT activation and NADPH oxidase expression and activity (7). Thus, SIRP␣ serves as an important modulator of the host adaptive immune response. Proteolysis and release of the SIRP␣ NH 2 -terminal domain has been demonstrated in primary cultured neurons, melanoma cells, and macrophage cell lines. Cleavage of murine SIRP␣ through an MMP inhibitor-sensitive pathway was first observed in cultured cells engineered to express both SIRP␣ and an active form of Ras (8). In these cells, blocking SIRP␣ proteolysis resulted in inhibited cell migration, cell spreading, and cytoskeletal reorganization. In addition, SIRP␣ was shown to regulate synaptic activity through activation of MMP inhibitor-sensitive prote...

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The Cytoplasmic Domain of A Disintegrin and Metalloproteinase 10 (ADAM10) Regulates Its Constitutive Activity but Is Dispensable for Stimulated ADAM10-dependent Shedding

Cited by 36 publications

References 41 publications

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

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