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The Journal of Immunology, 2009, 182, 49 -53
Copyright © 2009 by The American Association of Immunologists, Inc.
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Cutting Edge: The Metalloproteinase ADAM17/TNF-{alpha}-Converting Enzyme Regulates Proteolytic Shedding of the MHC Class I-Related Chain B Protein1

Philippe Boutet2,*, Sonia Agüera-González2,*, Susan Atkinson{dagger}, Caroline J. Pennington{ddagger}, Dylan R. Edwards{ddagger}, Gillian Murphy{dagger}, Hugh T. Reyburn* and Mar Valés-Gómez3,*

* Department of Pathology, University of Cambridge, Cambridge, United Kingdom; {dagger} Department of Oncology, Cancer Research U.K., Cambridge Research Institute, Cambridge University, Cambridge, United Kingdom; and {ddagger} School of Biological Sciences, University of East Anglia, Norwich, United Kingdom


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
MHC class I-related chain (MIC) A/B are transmembrane proteins expressed in pathological conditions that are ligands for the activating receptor NKG2D found on cytotoxic lymphocytes. Soluble NKG2D ligands are detected in sera of patients suffering from multiple types of cancer where they are associated with reduced levels of receptor expression and compromised function of NK and CTLs. In this study, we report the identification of a metalloproteinase involved in the cleavage process of MIC; inhibition and knockdown of ADAM17/TACE blocks the shedding of these proteins. Strikingly, the recruitment of both enzyme and substrate to detergent-resistant membrane microdomains is crucial for efficient proteolysis. These findings provide a novel insight into the molecular mechanisms of MIC shedding.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
The MHC class I-related chain (MIC)4 A and B proteins are polymorphic MHC-related molecules that bind the activating receptor NKG2D. Engagement of NKG2D by these ligands leads to the activation of lysis and cytokine secretion by NK cells and T cells and thus plays a central role in immune system activation (for review, see Refs. 1 and 2). The vast majority of healthy cells do not express MIC molecules and instead their expression at the cell surface is up-regulated in pathological situations like cancer and autoimmunity; so, broadly, MICA/B expression is related to stress, although much remains unclear about the molecular mechanisms regulating their expression (3).

The interaction between NKG2D and its ligands plays an important role in the immunosurveillance of cancer and tumor control. Thus, it is not surprising that tumor cells have evolved mechanisms to inhibit this system. Cytokines such as TGF-β can provoke down-regulation of NKG2D and its ligands (4, 5). Moreover, NKG2D ligands can be shed from tumor cells and have been detected in sera from patients with various types of cancer. Soluble NKG2D ligands appears to impair immune surveillance by promoting down-regulation of NKG2D (6), and high levels of soluble MIC (sMIC) molecules in sera correlate strongly with poor clinical outcome in patients suffering from various types of cancer, including colon (7) and prostate cancers (8). The mechanisms that regulate shedding of MICA/B are not well understood, but inhibition of cellular metalloproteinase activity markedly interferes with their release (9, 10, 11, 12), and recently shedding of MICA has also been shown to depend on ERp5, a thiol isomerase (13).

In this study, we report that the ADAM (a disintegrin and metalloproteinase) family member ADAM17, also known as TNF-{alpha}-converting enzyme (TACE), is involved in the shedding of soluble MICB and that regions of the membrane enriched in cholesterol and sphingolipids, also known as detergent-resistant membrane microdomains (DRMs), are an important site for this proteolysis.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Experimental procedures

A detailed description of the experimental procedures is provided in the supplemental data online.5

ELISA

sMICB was detected using a sandwich ELISA procedure. Plates were coated with an anti-MICB mAb from R&D Systems (5 µg/ml) and blocked with 2% BSA-PBS. Tissue culture supernatant was added for 1 h at 37°C. Bound MICB protein was detected using biotinylated goat anti-MICB (R&D Systems) followed by streptavidin-HRP (Amersham) and developed using the peroxidase substrate system (ABTS; Roche). The absorbance was measured at 410 nm with a reference wavelength of 490 nm. Samples were analyzed in duplicates. Under these conditions, the cutoff for detection of recombinant sMICB (BioSupply UK) was ~1 ng/ml and the ELISA absorbance values were directly proportional to the concentration of sMIC protein over the range of 1–100 ng/ml.

Small interfering RNA (siRNA) transfection

ADAM17/TACE and control siRNA were purchased from Dharmacon (catalog nos. D-001210-0101 and D-003453-04) (14). In some experiments, ADAM17 ON-TARGETplus SMARTpools from Dharmacon (catalog no. L-003453-00) were also used to knockdown expression of ADAM17. Cells, plated in 6-well plates, were transfected with either control or ADAM17-specific siRNA using Oligofectamine (Invitrogen) according to the manufacturer’s instructions. Seventy-two hours after transfection, cells were stimulated or not stimulated with PMA and then supernatants were harvested and cell lysates prepared for Western blot analysis.


   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Shedding of MICB is affected by metalloproteinase inhibitors and can be stimulated by PMA treatment

To characterize the shedding of MICA/B we analyzed the ability of inhibitors of different classes of proteases to affect MIC shedding from U373 and CV1 transfectants; BB94 and GM6001 inhibit both matrix metalloproteinases (MMPs) and some members of the ADAM family of proteases, leupeptin is an inhibitor of serine and cysteine proteinases, pepstatin inhibits aspartate proteinases. The metalloproteinase inhibitor BB94, but not inhibitors of other classes of proteases, dramatically decreased the shedding of MICB from both CV1/MICB cells (Fig. 1) and U373/MICB cells (data not shown). Similar data were obtained with MICA (supplemental Fig. 1A). Treatment with these inhibitors had no effect on cell viability or cell surface expression of MIC molecules (data not shown); thus, the reduction in the levels of released sMIC was due to the inhibition of sheddases and not toxicity. These results confirmed and extended previous studies (10), and posed the question of which metalloproteinase or metalloproteinases mediate shedding of MIC proteins.


Figure 1
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  		FIGURE 1. Shedding of MICB is sensitive to metalloproteinase inhibitors and can be stimulated by PMA treatment. A, MICB shedding is blocked by inhibitors of metalloproteinases (BB94) but not by serine, cysteine (leupeptin), or aspartate proteases (pepstatin A). B, Treatment with PMA but not ionomycin enhances shedding of MICB. C, Treatment with PMA leads to a loss of cell surface MICB that is blocked by incubation with metalloproteinase inhibitors. D, Incubation with TIMP3, but not TIMP1 or TIMP2, reduces shedding of MICB in the presence of PMA. The data shown in A and D are the average of three separate experiments. The data shown in B are representative of four experiments. Statistical significance was analyzed using a one-tailed Student’s t test; ***, p < 0.01.

 
Quantitative PCR to define the repertoire of metalloproteinases expressed by CV1 cells indicated that most members of the ADAM family and many MMPs were, expressed at high levels in this cell line (supplemental Fig. 1B). Thus, we tried to narrow down the list of candidate sheddases by testing the effect of pharmacological stimulation on metalloproteinase-mediated shedding of MICB. Phorbol esters are known to activate shedding of proteins mediated by ADAM17 (15), whereas Ca2+ ionophores activate ADAM10 (16). Shedding of MICB was increased after treatment with PMA, but not ionomycin (Fig. 1B), and was associated with a decrease in cell surface expression of MICB that was blocked by coincubation of PMA with metalloproteinase inhibitors (Fig. 1C). These observations are consistent with previous data on MICA (17) (supplemental Fig. 1C) and suggest that ADAM17 could be involved in sMICB release. To test this hypothesis, we assayed the ability of tissue inhibitor of metalloproteinases (TIMPs) to inhibit shedding of MICB. TIMPs are the major cellular inhibitors of the MMP subfamily and they inhibit active forms of all the MMPs studied to date, although with varying efficiencies. They also have inhibitory activity against some of the ADAMs, e.g., TIMP-3 inhibits ADAMs 10, 12, and 17 and the aggrecan-degrading enzymes ADAM-TS4 and -TS5 (where -TS indicates ADAM with a thrombospondin motif), whereas TIMP-1 inhibits ADAM10 and TIMP-2 inhibits ADAM12 (18). Addition of TIMP-3, but not TIMP-1 or -2 to CV1/MICB (Fig. 1D) and U373/MICB cells (supplemental Fig. 2) effectively reduced PMA-induced release of MICB, suggesting the involvement of ADAM17 in the shedding of sMICB. In our experiments, the presence of ERp5 could be considered a constant because ERp5 was expressed in both the CV1 and U373 cells used (data not shown). These experiments rule out the involvement of any of the other MMPs expressed by the cells that we have studied, but we cannot exclude the possibility that, in other cells expressing a distinct repertoire of metalloproteinases, enzymes other than ADAM17 could also be involved in cleavage of MICB.

ADAM17 mediates the shedding of MICB

The hypothesis that ADAM17 was critical for cleavage of MICB was confirmed by testing the effect of siRNA-mediated knockdown of this protease on the release of sMICB. Metalloproteinases are synthesized as proproteins that become active by proteolytic removal of the prodomain. Thus, in Western blotting two bands can be observed corresponding to the precursor and mature (active) forms of ADAM17, ~130 and ~100 kDa, respectively. In these knockdown experiments ADAM17, but not ADAM10, was specifically silenced (Fig. 2A). The decreased ADAM17/TACE expression despite an increase in enzyme activity after PMA treatment has been described previously (19) and is not well understood. In cells in which ADAM17 had been completely silenced, the amount of shed MICB decreased almost to background levels and PMA could not enhance the shedding of MICB in these cells (Fig. 2B). Similar data were obtained with a distinct set of siRNA specific for ADAM17 (not shown). That siRNA knockdown is more efficient than pharmacological inhibition of ADAM17 in blocking MIC shedding probably reflects the insolubility of the chemical inhibitors and the need to use lower than optimum concentrations of the compounds to avoid toxicity. These data clearly demonstrate that ADAM17 is involved in the release of sMICB. Similar data were obtained for MICA (supplemental Fig. 3).


Figure 2
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  		FIGURE 2. ADAM17 mediates the shedding of MICB. A, Specific silencing of ADAM 17. Cell lysates were prepared and analyzed for ADAM17, ADAM10, and β-actin expression by SDS-PAGE and Western blotting. B, siRNA-mediated silencing of ADAM17 markedly reduces both constitutive and PMA-induced shedding of MICB. Cells were transfected with control or ADAM17-specific siRNA. Seventy-two hours after transfection, the cells were washed and stimulated with PMA for 2 h. Supernatants were harvested and analyzed by ELISA. These data are representative of five separate experiments.

 
DRMs are a major site for proteolysis of MICB

Mature, active ADAM17 is present in DRMs (20), and so we hypothesized that the interaction of MICB with the metalloproteinase might occur in these specialized membrane domains rich in sphingolipids and cholesterol. If enzymatic cleavage of MICB occurred in DRMs, inhibition of the metalloproteinase to block shedding should increase the proportion of MICB found in DRMs. Indeed, in cells treated with PMA to enhance shedding, the presence of a broad spectrum metalloproteinase inhibitor (BB94) led to a clear increase in the proportion of MICB found in DRMs (Fig. 3A). A similar but less marked tendency was also seen when cells were treated with BB94 without exposure to PMA (supplemental Fig. 4). In agreement with the literature, active ADAM17 is seen to be enriched in DRMs.


Figure 3
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  		FIGURE 3. DRMs are major sites for proteolysis of MICB. A, MICB accumulates in DRMs upon metalloproteinase inhibition. Cells were incubated overnight with either PMA (100 ng/ml) alone or PMA and metalloproteinase inhibitor BB94 (10 µM). Cells were then lysed and fractionated by centrifugation on sucrose gradients. Equal volumes of these fractions were analyzed by dot or Western blotting for the indicated markers. B and C, ELISAs showing the effect of cholesterol depletion and palmitoylation inhibition on MICB shedding. CV1/MICB cells were either left untreated or treated with methyl-β-cyclodextrin (MβCD; 5 mM) or GM6001 (10 µM) for 1 h (B). Cells were cultured overnight either alone or with 2-bromo-palmitate (2-Br P; 100 µM) or GM6001 (10 µM) (C). The data shown in B and C are the average of four separate experiments. Statistical significance was analyzed using a one-tailed Student’s t test; ***, p < 0.01. D, MICB is lost from DRMs upon inhibition of palmitoylation. Cells were cultured overnight in medium alone or with 2-bromo-palmitate and then lysed and fractionated as above. Equal volumes of these fractions were analyzed by Western blotting for the indicated markers. Cav, Caveolin-1.

 
The shedding activity of ADAM17 for a variety of substrates is enriched in DRMs because the cleavage of the ADAM17 prodomain occurs in these membrane domains (20). Cholesterol depletion disrupts lipid rafts and provokes movement of the active form of ADAM17 into the nonraft region of the membrane (20). Given that the majority of MICB molecules are present in the nonraft region of the membrane, this displacement of ADAM17 might be predicted to trigger an increased release of these nonraft-located MICB proteins. Indeed, when CV1/MICB transfectants were depleted of cellular cholesterol by treatment with methyl-β-cyclodextrin, a moderate increase in shedding was observed (Fig. 3B). The capacity of different proteins to associate with DRMs varies, and their incorporation in lipid rafts is a dynamic process (21). One common mechanism by which transmembrane proteins are recruited to DRMs depends on modification by fatty acids, and MICA has been suggested to be palmitoylated (22). Treatment with a palmitate analog, 2-bromopalmitate, that effectively blocks fatty acylation in general and palmitoylation in particular (23) did not significantly reduce cell surface expression of MICB (mean fluorescence intensity of MICB on treated cells was 94 ± 14% of MICB expression on untreated cells) but did reduce the shedding of MICB almost as effectively as treatment with a metalloproteinase inhibitor (Fig. 3C), and this decrease in shedding was associated with a marked reduction in the amount of MICB found in DRMs (Fig. 3D).

These data strongly support the idea that recruitment of MICB to DRMs is important for efficient shedding of MICB and imply that the apparent low proportion of MICB in these membrane microdomains might simply reflect that molecules are cleaved there to be replaced by molecules coming from the nonraft region. These observations also suggest that MICB cleavage is regulated not only at the level of expression of the protease in the cell but also by encounter of ADAM17 with MICB in particular regions of the plasma membrane.

Biochemical analysis showed that the bulk of MICB present in tissue culture supernatant was a truncated species that remains soluble after centrifugation at 100,000 x g (Fig. 4A) and has a m.w. that corresponds to that of the cleaved protein. Because the glycan modifications of the sMICB present in supernatant were not susceptible to treatment with endoglycosidase H (Fig. 4B), these data support the hypothesis that cleavage of MIC occurs at the cell surface. Consistent with this idea, treatment of cells with brefeldin A did not block the accumulation of MICB in the supernatant (Fig. 4C).


Figure 4
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  		FIGURE 4. Biochemical characterization of sMICB. A, Shed MICB glycoproteins are soluble species. Cells were cultured overnight and, after that, total cell lysates (lanes marked "Lysate") and soluble proteins (lanes marked "Soluble") were analyzed by Western blotting. During the obtention of soluble proteins, a 10,000 x g centrifugation step was conducted to eliminate large membrane fragments from the tissue culture supernatant (10,000 x g). The pellet corresponding to this centrifugation step does not contain detectable amounts of MIC protein. Samples were digested with peptide-N-glycosidase F. B, Soluble MICB glycoproteins are resistant to endoglycosidase H (EndoH) digestion. Samples of cell lysates and soluble proteins were either left untreated or digested with EndoH and then analyzed by SDS-PAGE and Western blotting. C, Treatment of cells with 50 µg/ml brefeldin A or 100 µM chloroquine does not inhibit the accumulation of sMICB in tissue culture supernatant over time.

 
It has been reported that the inhibition of cellular metalloproteinase activity blocks the release of soluble NKG2D ligands (9, 10, 11), and the present data now show that ADAM17 is critically important for the shedding of sMICB.

Proteolytic shedding of ectodomains is an evolutionarily conserved posttranslational modification by which transmembrane molecules are converted into a soluble form. Cleavage and release of membrane proteins is a critical regulatory step in many normal and pathological processes that allows the cell to rapidly adapt the surface phenotype and generate soluble mediators to act on other cells. In the context of recognition of MICA/B proteins by the NKG2D receptor, shedding of sMIC represents a strategy by which a cell can evade immune recognition by NK cells and CTL. Removal of an activating ligand from the target cell surface reduces the possibility of recognition by cytotoxic effector cells. Moreover, because MICA/B proteins bind NKG2D with high affinity, shed MIC molecules can also go on to interact with NKG2D on cytotoxic lymphocytes to occupy free receptors and so compromise NKG2D-dependent recognition of target cells indirectly. Given the important role of NKG2D in the immunosurveillance of cancer, it is not surprising that many tumor cells have been reported to shed MIC proteins in vitro and that sMIC proteins have been found in the serum of patients suffering from multiple types of cancer. Indeed, analysis of large numbers of cancer patients has shown that elevated levels of sMICA and sMICB correlate significantly with cancer stage and metastasis (7, 8, 24, 25). Investigation of the molecular basis of the shedding of MICA/B proteins is thus of considerable interest and a deeper understanding of this process may allow the development of novel strategies for anticancer therapy.

Multiple studies have defined the importance of metalloproteinases in all major facets of cancer progression, including tumor growth, invasion, and metastasis, but the majority of clinical trials using broad-spectrum metalloproteinase inhibitors have proven disappointing. However, increased knowledge of the roles of metalloproteinases in tumor progression, combined with the use of more selective inhibitors, could lead to effective use of these compounds in therapies for cancer. In this context, our data may be useful in the rational design of new therapies based on metalloproteinase inhibition and, together with the recognized role of ADAM17 in tumor promotion via EGFR ligand release (26), endorse ADAM17 as a key target for cancer therapy.


   Acknowledgments
 
We thank Dr. F. Colucci and Prof. J. Trowsdale for critical reading of the manuscript and Dr. Neil Taylor for helpful advice.


   Disclosures
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 Abstract
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 Materials and Methods
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 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by grants from the Leukaemia Research Fund, The Newton Trust and the Medical Research Council. S.A.-G. is a recipient of a studentship from the Fundación Caja Madrid. D.R.E. and G.M. acknowledge support from the European Union Framework Programme 6 Cancer Degradome Project LSHC-CT-2003-503297. Back

2 P.B. and S.A.-G. contributed equally to the present work. Back

3 Address correspondence and reprint requests to Dr. Mar Valés-Gómez, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, U.K. E-mail address: mv231{at}cam.ac.uk Back

4 Abbreviations used in this paper: MIC, MHC class I-related chain; ADAM, a disintegrin and metalloproteinase; DRM, detergent-resistant membrane microdomain; MMP, matrix metalloproteinase; siRNA, small interfering RNA; sMIC, soluble MIC; TACE, TNF-{alpha}-converting enzyme; TIMP, tissue inhibitor of metalloproteinase. Back

5 The online version of this article contains supplemental material. Back

Received for publication July 2, 2008. Accepted for publication November 11, 2008.


   References
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 Abstract
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 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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