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*
Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan;
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and
Fukuoka Red Cross Blood Center, Chikushino, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-1-binding proteins on porcine uterus membranes
(2, 3). They have been identified in both vertebrates and
invertebrates so far (1). There is considerable evidence
showing that ficolins are lectins which have in common a specificity
for N-acetylglucosamine
(GlcNAc)3
(4, 5, 6, 7, 8, 9). The fibrinogen-like domain of ficolins is likely
to be responsible for exhibiting their lectin activity
(10). In humans, two kinds of serum ficolins,
L-ficolin/P35 (4) and H-ficolin
(5), and one kind of membrane-associated ficolin expressed
in lung and blood cells have been identified and characterized
(11, 12). The human serum ficolin
L-ficolin/P35 is a multimeric protein consisting of
35-kDa subunits. In addition to being a GlcNAc-binding lectin
(4), it also binds to elastin (13) and
corticosteroid (14). The L-ficolin/P35
functions as an opsonin when it binds certain types of oligosaccharides
on the surfaces of pathogens via its lectin activity
(4).
H-ficolin (also called Hakata Ag or thermolabile -2
macroglycoprotein) was first identified in serum as an Ag which is
recognized by an autoantibody in patients with systemic lupus
erythematosus (15). H-ficolin forms oligomers consisting
of 34-kDa subunits linked by disulfide bonds, like
L-ficolin/P35, and shows a ladder of >10 bands on SDS-PAGE under
nonreducing conditions (16). The primary structure of
H-ficolin has the characteristics of the ficolin family
(5), consisting of an NH2-terminal
region of 24 aa, a collagen-like domain with 11 Gly-Xaa-Yaa repeats, a
neck domain of 12 aa, and a fibrinogen-like domain of 207 aa. Its mRNA
is found in liver and lung (17). H-ficolin binds to GlcNAc
and N-acetylgalactosamine; therefore, it agglutinates
human erythrocytes coated with LPS derived from Salmonella
typhimurium, Salmonella minnesota, and Escherichia
coli (O111; Ref. 5).
Like ficolins, mannose-binding lectin (MBL), a member of the collectin family (18), is a serum-collagenous lectin which recognizes certain carbohydrates such as mannose and GlcNAc (19). MBL has several oligomeric forms with a subunit which has a carbohydrate-recognition domain as well as a collagen-like domain. Human MBL is complexed through its collagen-like domain with three types of C1r/C1s-like serine proteases, termed MBL-associated serine proteases (MASP) (20), MASP-1 (21, 22, 23), MASP-2 (24), and recently described MASP-3 (25). MBL is also associated with small MBL-associated protein (sMAP; also called MAp19), which is a truncated form of MASP-2 (26, 27). The composition of MASPs and sMAP in MBL-MASP complexes varies from oligomer to oligomer (25). MBL-MASP circulates in blood, and upon binding to pathogens via MBL, MASPs convert from an inactive proenzyme form consisting of a single polypeptide to an activated form containing two polypeptides linked by a disulfide bond, which has proteolytic activities. MASP-1 has proteolytic activities against C3 and C2 (28), MASP-2 cleaves C4 and C2 (24, 28, 29), and MASP-3 has inhibitory activity against MASP-2 (25). The function of sMAP in the complex is not known. Complement activation by MBL-MASP is called the lectin pathway and is the third pathway of activation.
In a previous paper, we demonstrated that L-ficolin/P35 is associated with MASP-1, MASP-2, and sMAP, and that L-ficolin/P35-MASP complexes activate complement, as does MBL (30). The activation of complement by L-ficolin/P35-MASP implies that L-ficolin/P35 is a collagenous lectin capable of activating the lectin pathway. Thus, L-ficolin/P35 may play a role in innate immunity by acting as an opsonin and activating the lectin pathway like MBL. In the present paper, we show that H-ficolin is another ficolin associated with MASPs and sMAP that activates the lectin pathway like MBL and L-ficolin/P35.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The pastes of Cohn III fraction from human plasma were kindly
provided by the Chemo-Sero-Therapeutic Research Institute, Kaketsuken
(Kumamoto, Japan). They were dissolved in 50 mM Tris, 200 mM NaCl, and
20 mM CaCl2, pH 7.8 (starting buffer). After
clotting, the filtrate was precipitated with 8% polyethylenglycol
4000. The precipitates were dissolved in starting buffer and then
applied to a GlcNAc-agarose column (Sigma Aldrich, St. Louis, MO).
MBL-MASP was eluted with starting buffer containing 0.3 M mannose.
L-ficolin/P35-MASP was then eluted with starting buffer
containing 0.15 M GlcNAc. MBL-MASP was purified further with monoclonal
anti-MBL (3E7)-Sepharose (21) and
L-ficolin/P35-MASP was purified further using Mono Q
(30). The pass-through fractions from the GlcNAc-agarose
column were used to purify H-ficolin. They were applied to monoclonal
anti-H-ficolin (4H5)-Sepharose equilibrated with 50 mM Tris, 200 mM
NaCl, and 10 mM CaCl2 (pH 7.8). H-ficolin was
eluted with 0.1 M Gly-HCl buffer (pH 2.2), and then neutralized with 1
M Tris-HCl buffer, pH 8.2 (5). After dialysis against 50
mM Tris, 200 mM NaCl, and 10 mM CaCl2 (pH 7.8),
the H-ficolin preparations were applied to Lentil lectin-Sepharose
(Amersham Pharmacia Biotech, Uppsala, Sweden) and eluted with 0.2 M
-methylmannopyranoside. To remove contaminating IgM and IgG in the
H-ficolin preparations, they were passed through anti-IgM-Sepharose
and protein A-Sepharose (Amersham Pharmacia Biotech) columns. The
H-ficolin preparations were then passed through anti-MBL
(3E7)-Sepharose and anti-L-ficolin/P35 (GN4)-Sepharose
(31).
Preparation of PSA, a polysaccharide produced by Aerococcus viridans
PSA, a polysaccharide produced by A. viridans, was prepared as described previously (32).
Immunoblotting
After SDS-PAGE (12% gel) under reducing conditions, proteins were transferred from the gels to polyvinylidene difluoride membranes and the blots were probed with Abs against MASPs. Abs against synthetic peptides representing the 19 C-terminal amino acids of MASP-1 (24) and the 19 N-terminal amino acids of MASP-3 (25) were provided by Dr. J. Jensenius (Aarhus University, Aarhus, Denmark). Ab against a synthetic peptide representing the 20 N-terminal amino acids of MASP-2/sMAP (30) was provided by Dr. I. Terai (Health Sciences University of Hokkaido, Sapporo, Japan). Peroxidase-conjugated secondary Abs were used and developed with a Konica Immunostaining HRP kit (Konica, Tokyo, Japan).
Assay of MASP activity
The following buffers were used for the assays of MASP activity. MGVB is a low ionic strength veronal-buffered saline containing 0.1% gelatin, 2.3% mannitol, 2 mM CaCl2, and 0.5 mM MgCl2 (pH 7.5). EDTA-GVB is veronal-buffered saline supplemented with 10 mM EDTA and 0.1% gelatin. For the C4 consumption assay, human C4 was incubated at 37°C for 30 min with H-ficolin preparations. The residual C4 activity was then determined hemolytically. The average number of hemolytic sites per cell (z) was calculated as: z = -ln (1 - y), where y is the hemolytic rate. The percentage of C4 consumed was calculated from z. To test the effect of anti-C1s on C4 consumption, H-ficolin preparations or human C1s were incubated at 37°C for 30 min with C4 in the presence of heat-inactivated polyclonal anti-C1s goat serum (Behringwerke, Marburg, Germany), and residual C4 activity was determined. For the C2 activation assay, Ab-sensitized sheep erythrocytes bearing guinea pig C1q and human C4b were incubated at 30°C for 15 min with H-ficolin preparations and oxidized human C2 in MGVB. Guinea pig serum diluted with EDTA-GVB was added to the reaction mixtures and they were incubated at 37°C for 60 min, after which EDTA-GVB was added, and z was determined. For the C3 cleavage assay, human C3 and H-ficolin preparations were incubated at 37°C for 60 min in VB-Ca. The reaction mixtures were then subjected to SDS-PAGE (7.5% gel) under reducing conditions. To assay C4 activation by the sold phase lectin-MASP complexes, ELISA plates were coated with monoclonal anti-H-ficolin (4H5), anti-MBL (3E7), or anti-L-ficolin/P35 (GN5). After blocking, H-ficolin preparations, MBL-MASP, or L-ficolin/P35-MASP diluted with TBST (50 mM Tris, 150 mM NaCl, 10 mM CaCl2, and 0.1% Tween 20, pH 7.5) were incubated at 37°C for 60 min in the wells. After washing the wells with TBST and then with MGVB, C4 was incubated at 37°C for 60 min in the wells. C4b deposition on the wells was detected by adding HRP-conjugated polyclonal anti-C4 and developing with ABTS. To assay C4 activation by H-ficolin preparations upon binding of H-ficolin to PSA, ELISA plates were first coated with PSA. After blocking, H-ficolin preparations diluted with TBST were incubated at 37°C for 60 min in the wells. The procedure for detecting C4b deposition on the wells was the same as that described above for C4 activation by Ab-bound H-ficolin preparations.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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H-ficolin was isolated from Cohn Fraction III using affinity
chromatography on monoclonal anti-H-ficolin-Sepharose and Lentil
lectin-Sepharose. To examine the H-ficolin preparations for the
presence of MASPs and sMAP, they were finally passed through
anti-L-ficolin/P35 and anti-MBL columns to ensure the
absence of L-ficolin/P35-MASP and MBL-MASP (Fig. 1
). The L-ficolin/P35-MASP and
MBL-MASP were also prepared from Cohn Fraction III as described in
Materials and Methods. As shown in Fig. 2, lane 1, Western blotting
analysis revealed that MASP-1 (L chain), MASP-2 (H chain), MASP-3 (L
chain), and sMAP were present in the H-ficolin preparations as in the
preparations of L-ficolin/P35-MASP and MBL-MASP.
Because the H-ficolin preparations were made using mAb against
H-ficolin, the presence of MASP-1, MASP-2, MASP-3, and sMAP in the
H-ficolin preparations indicates that H-ficolin was complexed with
these components (H-ficolin-MASP).
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We next determined whether MASPs in the H-ficolin-MASP complexes
were proteolytically active. MASPs are known to have proteolytic
activities against C4, C2, and C3. To examine C4 activation,
H-ficolin-MASP was incubated with C4 and the residual C4 hemolytic
activity was determined. H-ficolin-MASP consumed C4 in a dose-dependent
manner (Fig. 3A). C4
activation is ascribed to the proteolytic activity of MASP-2, but C1s
is another serine protease which can cleave C4. To exclude the
possibility that C4 consumption was mediated by C1s and not by MASP-2,
the effect of anti-C1s serum on C4 consumption was determined. It
was found that it did not inhibit C4 consumption by H-ficolin-MASP
under the conditions in which C4 consumption by C1s was completely
inhibited (data not shown). This indicates that C1s is not involved in
C4 activation by H-ficolin-MASP. C2 activation by H-ficolin-MASP was
assessed by the formation of a C3 convertase, C4b2a, on C4b-bearing
erythrocytes. As shown in Fig. 3B, C4b-bearing erythrocytes
were hemolyzed by incubating them with H-ficolin-MASP and C2 followed
by the addition of C3 to C9, indicating C2 activation by
H-ficolin-MASP. The proteolytic activity of H-ficolin-MASP against C3
was assessed by SDS-PAGE. H-ficolin-MASP cleaved C3 to generate the
'-chain of C3b in a dose-dependent manner (Fig. 3C).
These results indicate that MASPs present in the H-ficolin-MASP
complexes could cleave C4, C2, and C3 in the fluid phase.
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We next determined whether H-ficolin-MASP could activate
complement when the complex was bound to anti-H-ficolin Ab.
H-ficolin-MASP was incubated with anti-H-ficolin,
anti-L-ficolin/P35, or anti-MBL mAbs coated on ELISA
plates. Similarly, L-ficolin/P35-MASP and MBL-MASP were incubated
with the three kinds of mAbs as a control. C4 was then added to the
wells, and after further incubation, C4b deposition on the plates was
assessed. As shown in Fig. 4, H-ficolin-MASP activated C4 when H-ficolin was bound only to
anti-H-ficolin. Similarly, L-ficolin/P35-MASP and MBL-MASP
activated C4 when they were bound only to their corresponding Abs.
Although H-ficolin-MASP shows 
3-fold increase in the amount of C4
deposited compared with the deposition of C4 in the presence of
L-ficolin/P35-MASP or MBL-MASP, these three types of lectin-MASP
complexes are not comparable in efficiency in the activation of C4,
since the amount of the lectin-MASP complexes bound to Ab might not be
the same. The results shown in Fig. 4 confirm the formation of
complexes between H-ficolin and MASP-2, and also show that the
H-ficolin-MASP preparations did not contain L-ficolin/P35-MASP or
MBL-MASP.
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H-ficolin has been shown to bind to PSA, a polysaccharide produced
by A. viridans (32). PSA consists of repeating
units of glucose, mannose, GlcNAc, and xylose. Although the sugar
residue(s) responsible for H-ficolin binding has not been identified,
it is likely that H-ficolin binds to PSA via the lectin activity of its
fibrinogen-like domain. We determined whether H-ficolin-MASP activates
complement upon binding PSA. ELISA plates were first coated with PSA
and then H-ficolin-MASP was incubated in the wells. C4 was then added
to the wells, and after incubation, C4b deposition was assessed. As
shown in Fig. 5, H-ficolin-MASP bound to
PSA-activated C4. This indicates that upon binding to its ligand,
H-ficolin activates complement in association with MASP.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C1q, a subcomponent of C1 of the classical pathway, MBL, L-ficolin/P35, and H-ficolin are all oligomers and are similar in that they have a collagen-like domain within their subunits. These collagenous proteins are complexed with serine proteases which belong to the MASP/C1r/C1s family. Although it is most likely that the collagen-like domains of the four collagenous proteins are crucial for the binding of serine proteases (33), C1q differs from the other three collagenous proteins in that it is associated with C1r and C1s (34), and the others are associated with MASPs. The restricted binding specificities of the two types of serine proteases of the MASP/C1r/C1s family (C1r/C1s and MASPs) for the four collagenous proteins raises the possibility of a regulatory mechanism involved in complex formation. Although the lectin and the classical pathways in part share the activation mechanism, recent studies revealed that the MBL-mediated lectin pathway has unique features not possessed by the classical pathway. Three types of MASPs have been identified as serine proteases associated with MBL, while C1q is complexed with two types of serine proteases (C1r and C1s). MBL is also associated with a truncated form of MASP (sMAP), while the C1 complex does not contain such a truncated protein. MBL forms several types of oligomers and the composition of MASP binding to MBL varies from oligomer to oligomer (25). In contrast, C1q forms a hexameric oligomer and each oligomer is associated with C1r and C1s. The ficolins-mediated lectin pathway resembles the MBL-mediated lectin pathway in that like MBL, both L-ficolin/P35 and H-ficolin are complexed with three types of MASP and sMAP. Size heterogeneity was also found in human serum ficolins, especially in H-ficolin, suggesting a distinct MASP composition among the ficolin oligomers as is seen in the MBL oligomers.
As we demonstrated in this paper, one of the functions of human serum H-ficolin would be to activate the complement system through the lectin pathway. H-ficolin binds to PSA produced by A. viridans and activates complement. Therefore, it is conceivable that like the other lectins capable of activating the lectin pathway, H-ficolin plays a role in host defense against pathogens. H-ficolin is produced not only in liver, but also in lung. The functions of H-ficolin produced in lung remain to be elucidated. However, we can speculate that H-ficolin in lung, as well as serum H-ficolin, might act as an opsonin, as is the case with L-ficolin/P35 present in human serum. If this is the case, H-ficolin plays an important role in innate immunity in both blood and lung.
Both L-ficolin/P35 and H-ficolin bind to GlcNAc. Although studies comparing their precise specificities have not yet been conducted, their binding specificities appear to not be the same, because much smaller amounts of H-ficolin are obtained in the eluates with GlcNAc from the column compared with L-ficolin/P35 when purified using a GlcNAc column (data not shown). Therefore, the three collagenous lectins identified to date which can activate the lectin pathway might have both overlapping and distinct specificities for carbohydrates. The presence of these lectins might enable the host to eliminate pathogens on which various types of carbohydrates are present.
In conclusion, H-ficolin is the second lectin of the ficolin family which can activate the complement pathway in association with MASPs and sMAP. Our findings that two types of serum ficolins (L-ficolin/P35 and H-ficolin) are lectins that can activate the lectin pathway suggest that ficolins are a group of lectins that function in host defense. In this context, it is of particular interest to note that there are ficolins with lectin activity in the body fluid of ascidians (9). This suggests that ficolins have a crucial role in innate immunity, not only in vertebrates but also in invertebrates.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Misao Matsushita, Department of Biochemistry, Fukushima Medical University School of Medicine, 1-Hikariga-oka, Fukushima 960-1295, Japan. E-mail address: mmatsu{at}fmu.ac.jp
3 Abbreviations used in this paper: GlcNAc, N-acetylglucosamine; MBL, mannose-binding lectin; MASP, MBL-associated serine protease; sMAP, small MBL-associated protein; PSA, polysaccharide from Aerococcus viridans.
Received for publication December 21, 2001. Accepted for publication January 30, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 binding proteins from porcine uterus membranes. J. Biol. Chem. 266:22459.1-binding proteins. J. Biochem. 117:1029.1-binding proteins. FEBS Lett. 375:159.[Medline]
-2 macroglycoprotein ("thermolabile substance" or "Hakata antigen") detected by precipitating (auto) antibody in sera of patients with systemic lupus erythematosus. Biochim. Biophys. Acta 1078:369.[Medline]
-2 macroglycoprotein (Hakata antigen) by enzyme-linked immunosorbent assay using polysaccharide produced by Aerococcus viridans. Clin. Diagn. Lab Immunol. 8:454.
Asp allelic form of human mannose-binding protein (MBP) fails to bind MBP-associated serine protease. Biochem. J. 311:1021.
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J. S. Ferguson, J. J. Weis, J. L. Martin, and L. S. Schlesinger Complement Protein C3 Binding to Mycobacterium tuberculosis Is Initiated by the Classical Pathway in Human Bronchoalveolar Lavage Fluid Infect. Immun., May 1, 2004; 72(5): 2564 - 2573. [Abstract] [Full Text] [PDF]
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S. Zundel, S. Cseh, M. Lacroix, M. R. Dahl, M. Matsushita, J.-P. Andrieu, W. J. Schwaeble, J. C. Jensenius, T. Fujita, G. J. Arlaud, et al. Characterization of Recombinant Mannan-Binding Lectin-Associated Serine Protease (MASP)-3 Suggests an Activation Mechanism Different from That of MASP-1 and MASP-2 J. Immunol., April 1, 2004; 172(7): 4342 - 4350. [Abstract] [Full Text] [PDF]
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T. Ohashi and H. P. Erickson The Disulfide Bonding Pattern in Ficolin Multimers J. Biol. Chem., February 20, 2004; 279(8): 6534 - 6539. [Abstract] [Full Text] [PDF]
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N. J. Lynch, S. Roscher, T. Hartung, S. Morath, M. Matsushita, D. N. Maennel, M. Kuraya, T. Fujita, and W. J. Schwaeble L-Ficolin Specifically Binds to Lipoteichoic Acid, a Cell Wall Constituent of Gram-Positive Bacteria, and Activates the Lectin Pathway of Complement J. Immunol., January 15, 2004; 172(2): 1198 - 1202. [Abstract] [Full Text] [PDF]
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Y. Endo, M. Nonaka, H. Saiga, Y. Kakinuma, A. Matsushita, M. Takahashi, M. Matsushita, and T. Fujita Origin of Mannose-Binding Lectin-Associated Serine Protease (MASP)-1 and MASP-3 Involved in the Lectin Complement Pathway Traced Back to the Invertebrate, Amphioxus J. Immunol., May 1, 2003; 170(9): 4701 - 4707. [Abstract] [Full Text] [PDF]
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M. Kuraya, M. Matsushita, Y. Endo, S. Thiel, and T. Fujita Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G Int. Immunol., January 1, 2003; 15(1): 109 - 117. [Abstract] [Full Text] [PDF]
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S. Cseh, L. Vera, M. Matsushita, T. Fujita, G. J. Arlaud, and N. M. Thielens Characterization of the Interaction Between L-Ficolin/P35 and Mannan-Binding Lectin-Associated Serine Proteases-1 and -2 J. Immunol., November 15, 2002; 169(10): 5735 - 5743. [Abstract] [Full Text] [PDF]
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O. Neth, D. L. Jack, M. Johnson, N. J. Klein, and M. W. Turner Enhancement of Complement Activation and Opsonophagocytosis by Complexes of Mannose-Binding Lectin with Mannose-Binding Lectin-Associated Serine Protease After Binding to Staphylococcus aureus J. Immunol., October 15, 2002; 169(8): 4430 - 4436. [Abstract] [Full Text] [PDF]
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Y. Endo, M. Takahashi, M. Kuraya, M. Matsushita, C. M. Stover, W. J. Schwaeble, and T. Fujita Functional characterization of human mannose-binding lectin-associated serine protease (MASP)-1/3 and MASP-2 promoters, and comparison with the C1s promoter Int. Immunol., October 1, 2002; 14(10): 1193 - 1201. [Abstract] [Full Text] [PDF]
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