Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: Two genes, five proteins and many functions?

Yongqing, Tang; Drentin, Nicole C; Duncan, Robert J.; Wijeyewickrema, Lakshmi C.; Pike, Robert N.

doi:10.1016/j.bbapap.2011.05.021

Cited by 84 publications

(72 citation statements)

References 101 publications

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“…MASP-2 was also shown to cleave prothrombin in a similar way to activated factor X (FXa) and hence to promote clot formation (Krarup et al, 2007;Yongqing et al, 2012). In contrast, the function of MASP-3 remains unclear so far.…”

Section: Introductionmentioning

confidence: 99%

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MASP-1 of the complement system promotes clotting via prothrombin activation

Jenny

Dobó

Gál

et al. 2015

Molecular Immunology

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associated serine protease; MBL, mannose binding lectin; MCF, maximum clot firmness; MES, 2-(N-Morpholino)-ethanesulfonic acid; PAR4, protease activated receptor 4; PPP, platelet-poor plasma; PT-DP, Prothrombin-depleted plasma; PVDF, polyvinylidene difluoride; rMASP-1cf, MASP-1 catalytic fragment; SGMI, Schistocerca gregaria protease inhibitor (SGPI)-based MASPinhibitor; WB, whole blood. AbstractMannan-binding lectin-associated serine protease-1 (MASP-1), a protein of the complement lectin pathway, resembles thrombin in terms of structural features and substrate specificity, and it has been shown to activate coagulation factors. Here we studied the effects of MASP-1 on clot formation in whole blood (WB) and platelet-poor plasma (PPP) by thrombelastography and further elucidated the underlying mechanism. Cleavage of prothrombin by MASP-1 was investigated by SDS-PAGE and N-terminal sequencing of cleavage products. Addition of MASP-1 or thrombin to WB and PPP shortened the clotting time and clot formation time significantly compared to recalcified-only samples. The combination of MASP-1 and thrombin had additive effects. In a purified system, MASP-1 was able to induce clotting only in presence of prothrombin. Analysis of MASP-1-digested prothrombin confirmed that MASP-1 cleaves prothrombin at three cleavage sites. In conclusion, we have shown that MASP-1 is able to induce and promote clot formation measured in a global setting using the technique of thrombelastography. We further confirmed that MASP-1-induced clotting is dependent on prothrombin. Finally, we have demonstrated that MASP-1 cleaves prothrombin and identified its cleavage sites, suggesting that MASP-1 gives rise to an alternative active form of thrombin by cleaving at the cleavage site R393.

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Section: Introductionmentioning

confidence: 99%

“…In contrast, the function of MASP-3 remains unclear so far. It is speculated that MAp19 competes with the MASPs for the MBL binding site inhibiting activation of the lectin pathway (Dahl et al, 2001;Yongqing et al, 2012). MAp44 has also been shown to regulate the activity of the lectin pathway .…”

Section: Introductionmentioning

confidence: 99%

MASP-1 of the complement system promotes clotting via prothrombin activation

Jenny

Dobó

Gál

et al. 2015

Molecular Immunology

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“…PRMs of the LP are found in complexes with the MBL/ficolin-associated serine proteases (MASPs). Three catalytically active serine proteases (MASP-1, MASP-2, and MASP-3) and two alternative splice products (MAP-1 [MAp44] and sMAP [MAp19)] are known (24).…”

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confidence: 99%

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Pilely

Rosbjerg

Genster

et al. 2016

The Journal of Immunology

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Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind CC and function as an upstream innate inflammatory signal in the pathophysiology of atherosclerosis. We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3. MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis.

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“…In contrast to the proteases MASP-1 and MASP-2, for whom the enzymatic activities are well described, much less is known about MASP-3. MASP-3 may not be primarily involved in the activation of any downstream complement proteases 17,18 but may rather be involved in developmental processes. 33,34 MAp44 has no catalytic activity at all and is thought to exert biological functions only via binding to other proteins.…”

Section: Discussionmentioning

confidence: 99%

“…MBL circulates in plasma as a complex with MBL-associated proteases (MASPs) and MBL-associated proteins (MAps) that mediate or regulate downstream complement activation. 7,17,18 In humans, MASPs and MAps have been measured in case-control studies or during acute cardiovascular events (CVEs), [19][20][21] but longitudinal studies on the role of MASPs and MAps in CVD are not yet available.…”

mentioning

confidence: 99%

Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima–Media Thickness

Hertle

Arts

Kallen

et al. 2016

ATVB

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12associations with future CVD. When the effect of MBL on complications of established CVD was investigated, low MBL was in fact protective in most studies. [13][14][15] Thus, considerable discrepancy remains in the literature on whether MBL has beneficial or adverse effects in CVD.This reported discrepancy might be explained by a dual role of MBL in different etiologic aspects of CVD. Objective-Previous studies suggested that the lectin-complement pathway plays a complex role in cardiovascular disease (CVD). To date, no prospective human studies have investigated the relationship between the initiating factor of the lectin pathway, that is, mannose-binding lectin (MBL), and low-grade inflammation, endothelial dysfunction, or carotid intima-media thickness (cIMT). Moreover, MBL-associated proteases (MASPs) and MBL-associated proteins (MAps), which mediate downstream complement activation, have not been studied in the development of CVD. Approach and Results-In a prospective cohort (n=574; age 60±7 years; 7-year follow-up), we investigated longitudinal associations of plasma MBL, MASP-1, MASP-2, MASP-3, and MAp44 with biomarker scores that reflect low-grade inflammation and endothelial dysfunction, respectively, and with cIMT. We also investigated their associations with incident CVD (n=73). In adjusted analyses, low-grade inflammation was lowest in the middle tertile (T Middle )

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Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: Two genes, five proteins and many functions?

Cited by 84 publications

References 101 publications

MASP-1 of the complement system promotes clotting via prothrombin activation

MASP-1 of the complement system promotes clotting via prothrombin activation

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima–Media Thickness

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