Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein

Koike, Hisashi; TOMIOKA, Shigeo; Sorimachi, Hiroyuki; Saido, Takaomi C.; MARUYAMA, Kei; Okuyama, Atsushi; FUJISAWA-SEHARA, Atsuko; Ohno, Shigeo; Suzuki, Koichi; ISHIURA, Shoichi

doi:10.1042/0264-6021:3430371

Cited by 142 publications

(104 citation statements)

References 4 publications

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“…Interestingly, ADAM9 transient transfection also drastically increases sAPP␣ recovery in ␤APP-expressing HEK293 cells (Fig. 1, B and D), thereby confirming that in HEK293 cells, ADAM9 could participate to the ␣-secretase-mediated cleavage of ␤APP as it did in COS cells and human glioblastoma A172 cells (21,29).…”

Section: Transient and Stable Transfections Of Adam9 Cdna Increases N1supporting

confidence: 53%

“…Our study now clearly shows that ADAM9 contributes to the proteolytic processing of PrP c besides that of ␤APP suggested previously (21). However, our data did not establish whether catalysis triggered by ADAM9 was direct or indirect and one could not preclude a possible functional cross talk between disintegrins for PrP c and ␤APP proteolysis.…”

Section: Transient Transfection Of Adam9 Cdna Increases N1 and Sapp␣ contrasting

confidence: 43%

“…We identified ADAM10 and ADAM17, two members of the disintegrin and metalloprotease family (18), as the main enzymes responsible for constitutive and regulated production of N1, respectively (19). The nature of the disintegrins involved in N1 formation together with the PKC regulation of this cleavage were strikingly reminiscent of those taking place on ␤APP that ultimately leads to sAPP␣ secretion (20).Among the wide family of ADAM proteases, ADAM9 appeared as a likely candidate, particularly because this protease was suggested to contribute to sAPP␣ formation (21,22). Therefore, the close parallel between the ␣-secretases-generating sAPP␣ and N1 led us to postulate that ADAM9 could also contribute to N1 formation.…”

mentioning

confidence: 99%

“…Among the wide family of ADAM proteases, ADAM9 appeared as a likely candidate, particularly because this protease was suggested to contribute to sAPP␣ formation (21,22). Therefore, the close parallel between the ␣-secretases-generating sAPP␣ and N1 led us to postulate that ADAM9 could also contribute to N1 formation.…”

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confidence: 99%

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The Disintegrin ADAM9 Indirectly Contributes to the Physiological Processing of Cellular Prion by Modulating ADAM10 Activity

Cissé

Sunyach

Lefranc-Jullien

et al. 2005

Journal of Biological Chemistry

105

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The cellular prion protein (PrP c ) is physiologically cleaved in the middle of its 106 -126 amino acid neurotoxic region at the 110/ 1112112 peptidyl bond, yielding an N-terminal fragment referred to as N1. We recently demonstrated that two disintegrins, namely ADAM10 and ADAM17 (TACE, tumor necrosis factor alpha converting enzyme) participated in both constitutive and protein kinase C-regulated generation of N1, respectively. These proteolytic events were strikingly reminiscent of those involved in the socalled "␣-secretase pathway" that leads to the production of secreted sAPP␣ from ␤APP. We show here, by transient and stable transfection analyses, that ADAM9 also participates in the constitutive secretion of N1 in HEK293 cells, TSM1 neurons, and mouse fibroblasts. Decreasing endogenous ADAM9 expression by an antisense approach drastically reduces both N1 and sAPP␣ recoveries. However, we establish that ADAM9 was unable to increase N1 and sAPP␣ productions after transient transfection in fibroblasts depleted of ADAM10. Accordingly, ADAM9 is unable to cleave a fluorimetric substrate of membrane-bound ␣-secretase activity in ADAM10 ؊/؊ fibroblasts. However, we establish that co-expression of ADAM9 and ADAM10 in ADAM10-deficient fibroblasts leads to enhanced membrane-bound and released fluorimetric substrate hydrolyzing activity when compared with that observed after ADAM10 cDNA transfection alone in ADAM10 ؊/؊ cells. Interestingly, we demonstrate that shedded ADAM10 displays the ability to cleave endogenous PrP c in fibroblasts. Altogether, these data provide evidence that ADAM9 is an important regulator of the physiological processing of PrP c and ␤APP but that this enzyme acts indirectly, likely by contributing to the shedding of ADAM10. ADAM9 could therefore represent, besides ADAM10, another potential therapeutic target to enhance the breakdown of the 106 -126 and A␤ toxic domains of the prion and ␤APP proteins.Spongiform encephalopathies are fatal neurodegenerative diseases involving a highly protease-resistant protein referred to as prion scrapie (PrP sc ) 4 (1, 2). Human prion diseases include, among others, Creutzfeldt-Jakob disease, familial transmissible spongiform encephalopathies, new variant of Creutzfeldt-Jakob disease, as well as a few cases of iatrogenic transmission (3-5). PrP sc corresponds to the abnormal conformation of an ubiquitous glycosylphosphatidylinositol-anchored protein called cellular prion (PrP c ) that is mainly synthesized in the central nervous system (6, 7). The mechanisms by which PrP c is converted into PrP sc are not fully understood. However, it appears clearly that inoculation of PrP sc triggers pathology and ultimately cell death in mice only when PrP c is present in the host animal. Thus, PrP c null mice resist infection and toxicity exhibited by scrapie-enriched inoculates (8 -10). On the other hand, it appears that depletion of PrP c is relatively innocuous (11,12). Therefore, all strategies aimed at lowering endogenous PrP c are potential therapeutic approaches. Clas...

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Section: Transient and Stable Transfections Of Adam9 Cdna Increases N1supporting

confidence: 53%

Section: Transient Transfection Of Adam9 Cdna Increases N1 and Sapp␣ contrasting

confidence: 43%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Disintegrin ADAM9 Indirectly Contributes to the Physiological Processing of Cellular Prion by Modulating ADAM10 Activity

Cissé

Sunyach

Lefranc-Jullien

et al. 2005

Journal of Biological Chemistry

105

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“…Reagents and Antibodies-The following antibodies were used: anti-HA HA.11 (Covance) and 12CA5 (Roche), anti-FLAG (Sigma), anti-GFP (Clontech), anti-␤-actin, (Sigma), anti-calnexin (Stressgene), horseradish peroxidase-coupled goat anti-mouse and anti-rabbit (Promega), Alexa 555/Alexa 488-coupled secondary anti-mouse (Molecular Probes), Alexa 555-coupled secondary anti-rat antibody (Molecular Probes), Alexa 488-coupled anti-rabbit secondary antibody (Molecular Probes), anti-giantin (Alexis) (31), 6E10 (against A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] , Senetek Inc.), 6687 (against APP C terminus) (32), 22C11 (against APP ectodomain, provided by Konrad Beyreuther), 192wt (specific for the C terminus of APPs␤, provided by Dale Schenk), W02 (against amino acids 5-8 of A␤, provided by Konrad Beyreuther) (33), 3552 (against A␤ ) (34), (against N terminus of BACE1, Sigma), Nicastrin (N1660, Sigma), and the antibodies GM130, GS15, GS27, GS28, p230, Syntaxin 6, Vti1a, and Vti1b of the Golgi Sampler Kit, as well as the antibody against TGN38 (both BD Transduction Laboratories). Polyclonal TMEM59-antiserum 93 was generated against a synthetic peptide (H 2 N-309 -323-CONH 2 ) from the C terminus of TMEM59 (Eurogentec Seraing, Belgium), 3F4 (antimouse PrP) (35).…”

Section: Methodsmentioning

confidence: 99%

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

Ullrich

Münch

Neumann

et al. 2010

Journal of Biological Chemistry

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Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases ␣-and ␤-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid ␤ peptide (A␤). At present, little is known about the cellular mechanisms that control APP shedding and A␤ generation. Here, we identified a novel protein, transmembrane protein 59 (TMEM59), as a new modulator of APP shedding. TMEM59 was found to be a ubiquitously expressed, Golgi-localized protein. TMEM59 transfection inhibited complex N-and O-glycosylation of APP in cultured cells. Additionally, TMEM59 induced APP retention in the Golgi and inhibited A␤ generation as well as APP cleavage by ␣-and ␤-secretase cleavage, which occur at the plasma membrane and in the endosomes, respectively. Moreover, TMEM59 inhibited the complex N-glycosylation of the prion protein, suggesting a more general modulation of Golgi glycosylation reactions. Importantly, TMEM59 did not affect the secretion of soluble proteins or the ␣-secretase like shedding of tumor necrosis factor ␣, demonstrating that TMEM59 did not disturb the general Golgi function. The phenotype of TMEM59 transfection on APP glycosylation and shedding was similar to the one observed in cells lacking conserved oligomeric Golgi (COG) proteins COG1 and COG2. Both proteins are required for normal localization and activity of Golgi glycosylation enzymes. In summary, this study shows that TMEM59 expression modulates complex N-and O-glycosylation and suggests that TMEM59 affects APP shedding by reducing access of APP to the cellular compartments, where it is normally cleaved by ␣-and ␤-secretase. Processing of the amyloid precursor protein (APP)3 by two different proteases, called ␣-and ␤-secretase, is a central regulatory event in the generation of the amyloid ␤ peptide (A␤), which has a key role in Alzheimer disease (AD) pathogenesis (1). Both ␣-and ␤-secretase cleave the type I membrane protein APP within its ectodomain close to its transmembrane domain (2). This leads to the secretion of soluble forms of APP (APPs) and is referred to as APP shedding. The ␤-secretase is the aspartyl protease BACE1 and cleaves APP at the N terminus of the A␤ peptide domain, thus catalyzing the first step in A␤ peptide generation (3, 4). After the initial cleavage of APP by BACE1, the remaining C-terminal APP fragment is cleaved by ␥-secretase within its transmembrane domain at the C terminus of the A␤ domain, leading to the secretion of the A␤-peptide (5). In contrast to ␤-secretase, ␣-secretase cleaves within the A␤-sequence of APP, and thereby precludes A␤ peptide generation. Additionally, ␣-but not ␤-secretase cleavage generates a secreted form of APP (APPs␣), which has neurotrophic and neuroprotective properties (6 -8). The ␣-secretase is a member of the ADAM family (A disintegrin and metalloprotease) of proteases (9 -12). At present little is known about how the cell controls access of APP to its secretases and the amount of ␣-and ␤-secretase cleavage (reviewed in Refs. 13 and 14). Recent studies increasingl...

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(Make) Stick and cut loose—Disintegrin metalloproteases in development and disease

et al. 2006

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"A disintegrin and metalloprotease" (ADAM) proteases form a still growing family of about 40 type 1 transmembrane proteins. They are defined by a common modular ectodomain architecture that combines cell deadhesion/adhesion and fusion motifs (disintegrin and cysteine-rich domains), with a Zn-protease domain capped by a large prodomain. Their ectodomain thus strikingly resembles snake venom disintegrin proteases, which by combined integrin blocking and extracellular proteolysis, can cause extensive tissue damage after snake bites. A surprisingly large proportion (13 ADAMs) is exclusively expressed in the male gonads, and only a minority can be found throughout all tissues. As predicted by their amino acid sequence, a major proportion of this family has not maintained a functional protease domain, most probably rendering them into pure adhesion and/or fusion proteins. For most ADAMs, the respective key function has remained elusive. Despite their overall conserved ectodomain structure, ADAMs appear to be subdivided into those with a predominant role in direct adhesion (e.g., ADAMs 1, 2, and 3) and those mainly acting as proteases (e.g., ADAMs 10 and 17). Only for a few of them are functions of more than one domain documented (e.g., ADAM9 in cell fusion and proteolysis). Several ADAMs exist in both membrane-resident and secreted isoforms; the functional significance of this dichotomy is in most cases still unclear. Knockout phenotypes have been informative only in a few cases (ADAMs 1, 2, 10, 12, 15, 17, and 19) and are mainly related to their protease function. A common denominator of ADAM-mediated proteolysis is the ectodomain shedding of a broad spectrum of substrates, including paracrine growth factors like epidermal growth factor receptor (EGFR) ligands, cell adhesion molecules like CD44 or cadherins, and the initiation of regulated intramembrane proteolysis (RIP), whereby the transmembrane fragment of the respective substrate is further cleaved by an intramembrane cleaving protease to release an intracellular domain acting as a nuclear transcription regulator. Most ADAMs feature a significant overlap of substrate specificities, explaining why an inactivation of individual ADAMs only rarely causes major phenotypes.

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Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein

Cited by 142 publications

References 4 publications

The Disintegrin ADAM9 Indirectly Contributes to the Physiological Processing of Cellular Prion by Modulating ADAM10 Activity

The Disintegrin ADAM9 Indirectly Contributes to the Physiological Processing of Cellular Prion by Modulating ADAM10 Activity

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

(Make) Stick and cut loose—Disintegrin metalloproteases in development and disease

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