Mannose-Binding Lectin (MBL)-Associated Serine Protease (MASP)-1 Contributes to Activation of the Lectin Complement Pathway

Takahashi, Minoru; Iwaki, Daisuke; Kanno, Ken‐ichiro; Ishida, Yumi; Xiong, Jing; Matsushita, Misao; Endo, Yuichi; Miura, Shigeto; Ishii, N; Sugamura, Kazuo; Fujita, Teizo

doi:10.4049/jimmunol.180.9.6132

Cited by 149 publications

(153 citation statements)

References 28 publications

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“…Our findings are in agreement with a previous report that Masp1 gene knockout mice have a lowered lectin pathway activity (46), although these observations were confounded by the reported absence also of alternative pathway activity in these mice, because the alternative pathway is an important amplifier of the lectin and classical pathways. The crucial role of MASP-1 was surprising considering that both birds and fish seem to have lost the MASP-1-encoding exons by secondary genetic events subsequent to expansion of the MASPs (47)(48)(49).…”

Section: Discussionsupporting

confidence: 79%

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Degn

Jensen

Hansen

et al. 2012

The Journal of Immunology

142

152

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The lectin pathway of complement is an important component of innate immunity. Its activation has been thought to occur via recognition of pathogens by mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generating the C3 convertase. MASP-1 and MASP-3 are related proteases found in similar complexes. MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage. In mice, MASP-1 and MASP-3 have been reported to be central also to alternative pathway function through activation of profactor D and factor B. In this study, we present functional studies based on a patient harboring a nonsense mutation in the common part of the MASP1 gene and hence deficient in both MASP-1 and MASP-3. Surprisingly, we find that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, we find that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. We show that, although MASP-2 is able to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at physiological conditions through direct activation of MASP-2. We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that such cocomplexes are found in serum, providing a scenario for transactivation of MASP-2. Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s of the classical pathway.

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Section: Discussionsupporting

confidence: 79%

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Degn

Jensen

Hansen

et al. 2012

The Journal of Immunology

142

152

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“…From a functional standpoint, the ability of MASP-2 to trigger the lectin pathway of complement is clearly established (8). In contrast, whether MASP-1 is involved in this pathway is still a controversial issue (15,16), and the function of MASP-3 remains elusive.Studies on human (17-20) and rat (21, 22) proteins have established that the MASPs and MAp19 each associate as homodimers through their CUB 1 -EGF segment. In turn, the MASPs and MAp19 each form individual Ca 2ϩ -dependent complexes with MBL and the ficolins.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Crystal Structure of the CUB1-EGF-CUB2 Domain of Human MASP-1/3 and Identification of Its Interaction Sites with Mannan-binding Lectin and Ficolins

Teillet¹,

Gaboriaud

Lacroix³

et al. 2008

Journal of Biological Chemistry

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(CUB 2 ), plus one and two water molecules, respectively. To identify the residues involved in interaction of MASP-1 and -3 with MBL and L-and H-ficolins, 27 point mutants of human MASP-3 were generated, and their binding properties were analyzed using surface plasmon resonance spectroscopy. These mutations map two homologous binding sites contributed by modules CUB 1 and CUB 2 , located in close vicinity of their Ca 2؉ -binding sites and stabilized by the Ca 2؉ ion. This information allows us to propose a model of the MBL-MASP-1/3 interaction, involving a major electrostatic interaction between two acidic Ca 2؉ ligands of MASP-1/3 and a conserved lysine of MBL. Based on these and other data, a schematic model of a MBL⅐MASP complex is proposed.The lectin pathway of complement is increasingly recognized as an important component of innate immunity against pathogens. This pathway is triggered by oligomeric lectins that recognize patterns of neutral and acetylated carbohydrates on the surface of pathogens and share the ability to associate with and trigger activation of modular proteases termed mannanbinding lectin-associated serine proteases (MASPs) 3 (1, 2). Four such oligomeric lectins have been described: mannanbinding lectin (MBL) and ficolins L, H, and M (3-7). These proteins all assemble as oligomers of homotrimeric subunits, each comprising N-terminal collagen-like triple helices prolonged by recognition domains endowed with lectin-like binding activities. There are three different MASPs (MASP-1, -2, and -3) (4,8,9), and these feature modular structures homologous to those of C1r and C1s, the proteases of the C1 complex of complement, with an N-terminal CUB module (10), an epidermal growth factor (EGF)-like module belonging to the Ca 2ϩ -binding subset (11), a second CUB module, two complement control protein (CCP) modules (12), and a chymotrypsin-like serine protease domain. MASP-1 and MASP-3 are alternative splicing products of the MASP1/3 gene and include different serine protease domains but share identical CUB 1 -EGF-CUB 2 -CCP 1 -CCP 2 segments (9). Likewise, alternative splicing of the MASP2 gene generates MBL-associated protein 19 (MAp19), a truncated protein comprising the N-terminal CUB 1 -EGF segment of MASP-2 prolonged by four residues specific to MAp19 (13,14). From a functional standpoint, the ability of MASP-2 to trigger the lectin pathway of complement is clearly established (8). In contrast, whether MASP-1 is involved in this pathway is still a controversial issue (15,16), and the function of MASP-3 remains elusive.Studies on human (17-20) and rat (21, 22) proteins have established that the MASPs and MAp19 each associate as homodimers through their CUB 1 -EGF segment. In turn, the MASPs and MAp19 each form individual Ca 2ϩ -dependent complexes with MBL and the ficolins. The interaction involves a major site located in the CUB 1 -EGF moiety of each protein but is strengthened by module CUB 2 (18,19,22,23). Resolution of the x-ray structure of human MAp19 has allowed identification of a Ca 2ϩ...

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“…These results suggested that MASP-1 is not essential, but it facilitates the activation process. It was proposed that "MASP-1 contributes to the activation of the lectin pathway, probably through the activation of MASP-2" (Takahashi et al, 2008).…”

Section: Masp-2 Is Activated By Masp-1mentioning

confidence: 99%

Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

Dobó

Schroeder

Jenny

et al. 2014

Molecular Immunology

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MASP-1 is a versatile serine protease that cleaves a number of substrates in human blood. In recent years it became evident that besides playing a crucial role in complement activation MASP-1 also triggers other cascade systems and even cells to mount a more powerful innate immune response. In this review we summarize the latest discoveries about the diverse functions of this multi-faceted protease. Recent studies revealed that among MBLassociated serine proteases, MASP-1 is the one responsible for triggering the lectin pathway via its ability to rapidly autoactivate then cleave MASP-2, and possibly MASP-3. The crystal structure of MASP-1 explains its more relaxed substrate specificity compared to the related complement enzymes. Due to the relaxed specificity, MASP-1 interacts with the coagulation cascade and the kinin generating system, and it can also activate endothelial cells eliciting pro-inflammatory signaling.

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Mannose-Binding Lectin (MBL)-Associated Serine Protease (MASP)-1 Contributes to Activation of the Lectin Complement Pathway

Cited by 149 publications

References 28 publications

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Crystal Structure of the CUB1-EGF-CUB2 Domain of Human MASP-1/3 and Identification of Its Interaction Sites with Mannan-binding Lectin and Ficolins

Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

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