Human Molecular Genetics, 2001, Vol. 10, No. 15 1563-1569
© 2001 Oxford University Press
Processing of ß-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex
Department of Neurology and Neuroscience, Teikyo University School of Medicine, Tokyo 173-8605, Japan, 1Banyu Tsukuba Research Institute, Tsukuba, Ibaraki 300-2611, Japan and 2Shionogi Research Laboratories, Shionogi & Co. Ltd, Osaka 553-0002, Japan
Received April 4, 2001; Revised and Accepted May 25, 2001.
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ABSTRACT |
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The dystroglycan complex is a membrane-spanning complex composed of two subunits,
- and ß-dystroglycan. -dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), whereas ß-dystroglycan is an integral membrane protein which anchors -dystroglycan to the cell membrane. The dystroglycan complex provides a tight link between the ECM and cell membrane. Dysfunction of the dystroglycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary neuromuscular diseases, including Duchenne muscular dystrophy, Fukuyama-type congenital muscular dystrophy and sarcoglycanopathy (LGMD2C, -D, -E and -F). To begin to clarify the pathway by which the dysfunction of the dystroglycan complex could lead to muscle cell degeneration, we investigated the proteolytic processing of the dystroglycan complex in this study. We demonstrate that (i) a 30 kDa fragment of ß-dystroglycan is expressed in peripheral nerve, kidney, lung and smooth muscle, but not skeletal muscle, cardiac muscle or brain, and (ii) this fragment is the product of proteolytic processing of the extracellular domain of ß-dystroglycan by the membrane-associated matrix metalloproteinase (MMP) activity. Importantly, furthermore, we demonstrate that this processing disintegrates the dystroglycan complex. Our results indicate that the processing of ß-dystroglycan by MMP causes the disruption of the link between the ECM and cell membrane via the dystroglycan complex, which could have profound effects on cell viability. Based on these and previously reported findings, we propose a hypothesis that this processing may play a crucial role in the molecular pathogenesis of sarcoglycanopathy. |
INTRODUCTION |
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Dystroglycan is expressed in a wide variety of tissues at the interface between the basement membrane and cell membrane linking the extracellular matrix (ECM) to the intracellular cytoskeleton. Dystroglycan is formed as one precursor protein and cleaved into two mature proteins (1,2). One is the cell surface component
-dystroglycan, which binds to the major basal lamina components; laminin, agrin and perlecan (for a review, see ref. 3). The other is the transmembrane component ß-dystroglycan, which anchors -dystroglycan to the cell membrane via the N-terminus of the extracellular domain and binds to cytoskeletal proteins, dystrophin and its homologs, via the C-terminal cytoplasmic domain (4–6). The dystroglycan complex serves as a scaffold for the assembly of the basement membrane in early development and is maintained as a tight link between the basement membrane and cytoskeleton thereafter (3,7–11).
Thus far, genetic defects of dystroglycan have not been reported as the primary cause of hereditary diseases in humans, probably due to the fact that a null mutation of dystroglycan causes premature death of embryos (8,11). Interestingly, however, secondary abnormalities of dystroglycan have been described in a number of severe forms of hereditary neuromuscular diseases. For instance, the expression of dystroglycan has been shown to be greatly disturbed in the skeletal muscle of the patients with Duchenne muscular dystrophy (DMD) and Fukuyama-type congenital muscular dystrophy (FCMD) (12–14). The other intriguing example is sarcoglycanopathy (LGMD2C, -D, -E and -F), which is characterized by deficiency of the sarcoglycan complex comprised of -, ß-, 
- and 
-sarcoglycan due to the primary genetic defects of these proteins (for reviews, see refs 15–18). It was reported recently that a proteolytic fragment of dystroglycan was observed in the skeletal muscle of the patients with sarcoglycanopathy specifically (19). These findings could provide us with important clues to better understand the precise molecular pathways by which the primary genetic defects lead to muscle cell degeneration in these diseases.
The fact that the dystroglycan complex provides a tight link between the ECM and cell membrane indicates that this structure needs to be disrupted efficiently when tissue remodeling takes place in both physiological and pathological conditions. Therefore, it is not hard to imagine that a specific device exists to disrupt this structure. Moreover, it would be intriguing to hypothesize that this device may also play a role in the molecular pathogenesis of the aforementioned neuromuscular diseases. To begin to address these possibilities, we investigated the proteolytic processing of the dystroglycan complex and its effects on the function of the complex in this study.
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RESULTS |
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Tissue distribution of the 30 kDa fragment of ß-dystroglycan
The skeletal muscle ß-dystroglycan is detected as a single 43 kDa band (ß-DGfull) by immunoblot analysis using the monoclonal antibody 43DAG/8D5 against the C-terminal cytoplasmic tail of ß-dystroglycan (19). However, we and others have reported that, in addition to ß-DGfull, 43DAG/8D5 also detects a 30 kDa fragment of ß-dystroglycan (ß-DG30) in certain tissues and cultured cells (19–22). To know the tissue distribution of ß-DG30, we prepared the total homogenates of various bovine tissues and performed immunoblot analysis using 43DAG/8D5. ß-DG30 was clearly detected in peripheral nerve, smooth muscle (bladder), lung and kidney, whereas it was obscure or undetectable in cardiac muscle, skeletal muscle, cerebrum and cerebellum (Fig. 1A).
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Extraction profile of ß-DG30
Extraction analysis of membrane-associated proteins is effective for clarifying their biochemical properties in relation to the membrane lipid bilayer. For instance, it is well established that integral membrane proteins are extracted by non-ionic detergents such as Triton X-100, whereas peripheral membrane proteins are extracted by high alkaline conditions (4,23). It is also known that some ECM proteins, but not integral and peripheral membrane proteins, are extracted by EDTA (23,24). To compare the biochemical properties of ß-DG30 with ß-DGfull, we performed the extraction analysis of the crude membranes of bovine peripheral nerve and rat RT4 schwannoma cells, which express both ß-DGfull and ß-DG30. Bovine peripheral nerve ß-DGfull and ß-DG30 showed identical extraction profiles. They were both extracted by 2% Triton X-100 and high ionic strength enhanced the effect of the detergent (Fig. 1B). However, they were not extracted by pH 11 or by 10 mM EDTA (Fig. 1B). Similar results were obtained with RT4 cells (Fig. 1C). Because ß-dystroglycan is a type I integral membrane protein with a single transmembrane domain, these results indicate that ß-DG30 retains this transmembrane domain. Also, because ß-DG30 is recognized by 43DAG/8D5 directed against the C-terminus of the cytoplasmic domain of ß-dystroglycan, these results indicate that the predicted cleavage site exists in the extracellular domain of ß-dystroglycan and that ß-DG30 is its C-terminal fragment.
ß-DG30 is the processing product of ß-DGfull by the matrix metalloproteinase (MMP) activity
We suspected that MMP activity might be responsible for the processing of ß-DGfull into ß-DG30, because the cleavage site was predicted to exist in the extracellular domain of ß-dystroglycan. To test this hypothesis, we cultured RT4 cells in the presence or absence of two highly specific MMP inhibitors, N-biphenyl-sulfonyl-phenylalanine hydroxamic acid (BPHA) and L-N-(N-hydroxy-2-isobutylsuccinamoyl)-leucyl isobutyl amido (SI-27), harvested the living cells and performed the immunoblot analysis. ß-DG30 decreased with increasing concentrations of BPHA or SI-27 (Fig. 2A). These results indicate (i) that ß-DG30 is indeed the MMP processing fragment and (ii) that this MMP is active for the living RT4 cells.
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To clarify whether the MMP activity is present in RT4 cells themselves or secreted into the culture medium, RT4 cells were harvested, homogenized and then incubated at 37°C for various times. As shown in Figure 2B, ß-DGfull decreased and ß-DG30 increased with time, indicating that the MMP activity was present in RT4 cells themselves, not completely secreted into the culture medium. To test the membrane association of the MMP activity, we prepared the membrane fractions from the harvested RT4 cells in the presence or absence of BPHA or SI-27 and compared the results. The MMP activity was significantly reduced with BPHA (Fig. 2C) or SI-27 (data not shown), suggesting that the MMP activity was membrane-associated.
The MMP cleavage disintegrates the dystroglycan complex
To find out whether the processing of ß-dystroglycan by the MMP activity affects the integrity of the dystroglycan complex, we checked the composition of the dystroglycan complex isolated from RT4 cells. First, we solubilized the RT4 cell membrane fractions with a mild detergent, digitonin, and isolated the dystroglycan complex from the digitonin extracts by laminin affinity chromatography. As shown in Figure 3A, ß-DGfull co-isolated with -dystroglycan, which bound to laminin–Sepharose directly as a laminin-binding protein. However, ß-DG30 did not co-isolate with -dystroglycan (Fig. 3A). Secondly, we applied the digitonin extracts of RT4 cell membrane fractions to wheatgerm agglutinin (WGA) affinity chromatography to isolate the glycosylated proteins. -dystroglycan, ß-DGfull and ß-DG30 were all absorbed by WGA–Sepharose in this condition and recovered in the eluates (data not shown). To separate the negatively charged glycoproteins, we then applied the WGA eluates to strong anion-exchange chromatography and eluted with a 0–1 M NaCl concentration gradient. The dystroglycan complex, comprised of -dystroglycan and ß-DGfull, was recovered with a peak in the 0.35 M NaCl elution (Fig. 3A). However, ß-DG30 was not detected in the isolated dystroglycan complex (Fig. 3A). Instead, ß-DG30 was recovered with a peak in the 0.17 M NaCl elution (data not shown). Finally, we used a harsher detergent, Triton X-100, to solubilize the dystroglycan complex from the RT4 cell membrane fractions. When the Triton X-100 extracts were applied to WGA affinity chromatography, -dystroglycan and ß-DGfull were completely absorbed by WGA–Sepharose and recovered in the eluates (Fig. 3B). However, ß-DG30 was not absorbed, and undetectable in the eluates (Fig. 3B). Altogether, these results indicate that ß-DGfull, but not ß-DG30, is complexed with -dystroglycan and thus that the MMP cleavage of ß-dystroglycan into ß-DG30 disintegrates the dystroglycan complex.
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The reason why ß-DG30 solubilized by digitonin, but not by Triton X-100, bound to WGA–Sepharose is unclear. ß-DG30 is predicted to lack a portion of the highly glycosylated N-terminus of ß-dystroglycan (1,2). Therefore, ß-DG30 is expected to have less affinity to WGA–Sepharose than ß-DGfull. This is consistent with the fact that ß-DG30 was eluted from the strong anion-exchange chromatography by a relatively low NaCl concentration, which indicates that ß-DG30 is not highly negatively charged due to less glycosylation. One possible explanation could be that ß-DG30 solubilized by digitonin, which is a far milder detergent than Triton X-100, was associated very weakly with some other WGA-binding glycoproteins, and that this association was disrupted by Triton X-100. Alternatively, it is also possible that, due to less glycosylation, ß-DG30 could bind to WGA–Sepharose independently only when solubilized by a mild detergent such as digitonin.
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DISCUSSION |
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BPHA and SI-27 are the MMP inhibitors which have a very narrow range of target specificity (Table 1) (25–28). Thus, the fact that both BPHA and SI-27 inhibited the cleavage of ß-DGfull into ß-DG30 indicates that ß-DG30 is the product of proteolytic processing of ß-DGfull by MMP activity. Although the exact cleavage site in ß-dystroglycan remains to be determined, the fact that ß-DG30 showed an extraction profile identical to that of ß-DGfull indicates that ß-DG30 retains the single transmembrane domain of ß-dystroglycan. Together with the facts that ß-dystroglycan is a type I membrane protein and that ß-DG30 is recognized by 43DAG/8D5 directed against the C-terminus of the cytoplasmic domain of ß-dystroglycan, this predicts that the cleavage site exists in the extracellular domain of ß-dystroglycan and ß-DG30 is its C-terminal fragment. This is consistent with the fact that the MMP is responsible for this processing. We have also found that this MMP activity is membrane-associated, not completely secreted into the culture medium.
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The fact that both BPHA and SI-27 inhibited the processing of ß-dystroglycan in the living cells suggests that this MMP is active in vivo. What effects does this processing have in vivo? The finding that ß-DG30 was not complexed with
-dystroglycan indicates that the cleavage of ß-DGfull into ß-DG30 disintegrates the dystroglycan complex. Because - and ß-dystroglycan are responsible for the binding to the basement and cell membranes, respectively, this cleavage will disrupt the link between the basement and cell membranes (Fig. 4B). This is also consistent with the recent report that the -dystroglycan-binding site exists in the N-terminus of the extracellular domain of ß-dystroglycan (6), because ß-DG30 is the C-terminal fragment of the cleavage, as discussed above.
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These findings will have important implications in an array of biological phenomena. For instance, it has been shown recently that certain carcinoma cell lines express ß-DG30 abundantly (22). Taken together with our results, carcinoma cells are presumed to employ the MMP activity to disrupt the dystroglycan complex. This will enable carcinoma cells to metastasize and invade other tissues. Interestingly in this respect, both BPHA and SI-27, the MMP inhibitors which we used in this study, have been developed as drugs to inhibit cancer spread and metastasis (25–28). The processing of ß-dystroglycan by MMP may also play a role in the molecular pathogenesis of viral and bacterial infection. It has been shown recently that pathogens such as arena viruses (several strains of lymphocytic choriomeningitis virus and Lassa fever virus) and Mycobacterium leprae bind to the cell surface
-dystroglycan as an initial step of host cell infection (29–31). Therefore, the MMP activity responsible for ß-DG30 may be a natural defence mechanism against these pathogens, in analogy to matrilysin (MMP-7) which has been shown recently to play a defensive role against microorganisms in mucosal epithelial cells (32). Another intriguing example where the processing of ß-dystroglycan by MMP is implicated is the molecular pathogenesis of hereditary neuromuscular diseases. Over the last 10 years, primary genetic defects have been identified in a number of these diseases. However, the precise molecular pathways by which the primary defects eventually lead to muscle cell degeneration in these diseases have not necessarily been clarified. Studies to elucidate the biological functions and dysfunctions of the proteins that work in close concert with the causative proteins in vivo can be quite useful in this context. As such, research on the proteolytic processing of dystroglycan could provide us with precious clues concerning the molecular pathogenesis of severe forms of muscular dystrophies caused by the primary defects of the components of the dystrophin-glycoprotein complex and its related proteins, because abnormalities of dystroglycan are well known in these diseases. For instance, the expression of dystroglycan has been shown to be greatly disturbed in the biopsied skeletal muscle of the patients with DMD and FCMD (12–14). Most interestingly, the proteolytic fragment of ß-dystroglycan corresponding to ß-DG30 has been detected in the biopsied skeletal muscle of the patients with sarcoglycanopathy (19). This observation was specific to sarcoglycanopathy and not found in a variety of other neuromuscular diseases (19). Together with our results, these findings indicate that the MMP processing of ß-dystroglycan is activated in sarcoglycanopathy skeletal muscle.
At present, the molecular mechanism by which the deficiency of the sarcoglycan complex leads to muscle cell death in sarcoglycanopathy remains unclear. However, several lines of evidence indicate that the deficiency of the sarcoglycan complex causes the disintegration of the dystroglycan complex in sarcoglycanopathy. First, -dystroglycan has been reported to be reduced in the skeletal muscle of patients with sarcoglycanopathy (17,33,34). Secondly, -dystroglycan was dissociated from ß-dystroglycan and not recovered in the membrane fraction of striated muscle of the BIO 14.6 cardiomyopathic hamsters and sarcoglycanopathy patients (35,36). Thirdly, -dystroglycan was not recovered in the sarcolemma fraction and released into the supernatant of membrane preparations in -sarcoglycan knockout mice (37). Finally, -dystroglycan, which was dissociated from the other components of the dystrophin-glycoprotein complex in striated muscle of BIO 14.6 cardiomyopathic hamsters, was reconstituted into the complex when the whole sarcoglycan complex was restored by the adenovirus transfer of the -sarcoglycan gene (38).
Taking all these findings into account, we hypothesize (i) that the sarcoglycan complex masks the MMP cleavage site on ß-dystroglycan in normal skeletal muscle (Fig. 4A) and (ii) that the deficiency of the sarcoglycan complex in sarcoglycanopathy induces the MMP processing of ß-dystroglycan, causing the disruption of the link between the basement membrane and sarcolemma (Fig. 4B). Thus far, there are very few studies implicating the MMP activity in the pathogenesis of muscular dystrophies. Recently, however, Lattanzi et al. (39) reported the aberrantly processed laminin 2 chain and increased activity of MMP-2/MMP-14 in the cultured skeletal muscle cells from the patients with congenital muscular dystrophy. Because the condition was characterized by the partial deficiency of laminin-2/4, their findings suggest that these MMPs may play a role in the molecular pathogenesis of muscle cell death in this condition (39).
Finally, what type of MMP is responsible for the processing of ß-dystroglycan? Considering the profile of inhibitory activity of the two MMP inhibitors we used, MMP-2/MMP-14 and MMP-9 should be listed among the candidates (Table 1). It is also possible that a hitherto unidentified MMP may be responsible. In any case, identification of the MMP awaits future studies. In this respect, our finding that this MMP activity was associated with the RT4 cell membrane, not completely secreted into the culture medium, will help us in planning further strategies. Such a study will be important, because it may lead to the development of novel pharmacological therapies to prevent not only cancer invasion and metastasis but also muscle cell degeneration in muscular dystrophies.
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MATERIALS AND METHODS |
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Miscellaneous
Three to 15% SDS–PAGE and immunoblotting were performed as described previously (20,23,40,41), except that immunoblot development was performed by chemiluminescence using ECL reagents (Amersham Pharmacia Biotech, Little Chalfont, UK). The luminescence was detected and visualized by Image Station 440 system (Eastman Kodak Company, New Haven, CT). The monoclonal antibody 43DAG/8D5 against the C-terminal 15 amino acids of ß-dystroglycan and IIH6 against
-dystroglycan are kind gifts from Drs L.V.B. Anderson (Newcastle General Hospital) and K.P. Campbell (University of Iowa), respectively (1,19–21,42). Bovine peripheral nerve, cerebrum, cerebellum, skeletal muscle, heart, bladder, kidney and lung were obtained freshly at a local abattoir. The rat schwannoma cell line RT4 was kindly provided by Drs A. Asai (University of Tokyo) and Y. Kuchino (National Cancer Center, Tokyo) (43,44). RT4 cells were grown in Dulbecco’s modified Eagle’s medium containing 10% fetal calf serum, 16.7 mM glucose, 2 mM glutamine, 100 U/ml penicillin G sodium and 100 µg/ml streptomycin. Culture medium was changed every 3 days. When RT4 cells grew to near confluence, culture medium was discarded by decanting and living cells were harvested by scraping the culture dishes with rubber policemen. The crude membrane fractions of bovine peripheral nerve and RT4 cells were prepared as described previously (20,23,41,44). Extraction of the crude membrane fractions under various conditions was performed as described previously (20,23,41).
BPHA and SI-27 have been developed recently as the specific inhibitors of MMP, which have not only very narrow ranges of target specificity but also very low levels of cytotoxicity (25–28). The profile of inhibitory activities of these reagents is summarized in Table 1.
Isolation of the dystroglycan complex
(i) Laminin affinity chromatography. Ten milligrams of RT4 cell membranes were extracted at the protein concentration of 5 mg/ml in a buffer containing 1% digitonin, 50 mM Tris–HCl pH 7.4, 140 mM NaCl, 1 mM CaCl2 and a cocktail of protease inhibitors (0.75 mM benzamidine, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.7 µM pepstatin A, 76.8 nM aprotinin and 1.1 µM leupeptin) at 4°C for 2 h. After centrifugation at 140 000 g for 30 min at 4°C, the supernatant was incubated overnight at 4°C with 200 µl of laminin–Sepharose, which was prepared as described previously (41). After extensive washing with a buffer containing 0.1% digitonin, 50 mM Tris–HCl pH 7.4, 140 mM NaCl, 0.75 mM benzamidine, 0.1 mM PMSF and 1 mM CaCl2, the bound fractions were eluted by a buffer containing 0.1% digitonin, 50 mM Tris–HCl pH 7.4, 0.75 mM benzamidine, 0.1 mM PMSF and 10 mM EDTA.
(ii) WGA affinity chromatography followed by strong anion-exchange chromatography. Fifty milligrams of RT4 cell membranes were extracted at the protein concentration of 5 mg/ml in a buffer containing 1% digitonin or Triton X-100, 120 mM NaCl and the aforementioned cocktail of protease inhibitors at 4°C for 2 h. After centrifugation at 140 000 g for 30 min at 4°C, the supernatant was incubated with 2 ml of WGA–Sepharose 6MB (Amersham Pharmacia Biotech) overnight at 4°C. After extensive washing with a buffer containing 0.1% digitonin or Triton X-100, 50 mM Tris–HCl pH 7.4, 120 mM NaCl, 0.75 mM benzamidine and 0.1 mM PMSF, the bound fractions were eluted by a buffer containing 0.1% digitonin or Triton X-100, 50 mM Tris–HCl pH 7.4, 0.35 M N-acetyl-D-glucosamine, 0.75 mM benzamidine and 0.1 mM PMSF. In the case of digitonin extraction, the WGA eluates were then applied to 400 µl of Source Q15 strong anion-exchange column (Amersham Pharmacia Biotech). After extensive washing with a buffer containing 0.1% digitonin, 50 mM Tris–HCl pH 7.4, 0.75 mM benzamidine and 0.1 mM PMSF, the bound fractions were eluted by 0–1 M NaCl concentration gradient in a buffer containing 0.1% digitonin, 50 mM Tris–HCl pH 7.4, 0.75 mM benzamidine and 0.1 mM PMSF.
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ACKNOWLEDGEMENTS |
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We thank Dr S. Ishiura (University of Tokyo) for helpful discussion and advice. This work was supported by Research Grants 10B-3 and 11B-1 for Nervous and Mental Disorders, Health Sciences Research Grant for Research on Brain Science, H12-Brain-017, from the Ministry of Health, Labor and Welfare, and Research Grants 09470156, 09770460, 09877121, 10044319, 11470151, 11670644 and 12470143 from the Ministry of Education, Sports, Culture, Science and Technology.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +81 3 3964 1211; Fax: +81 3 3964 6394; Email: k-matsu@med.teikyo-u.ac.jp
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