Vitronectin-mediated inhibition of complement: evidence for different binding sites for C5b-7 and C9

Milis, L.; Morris, Carol A.; Sheehan, M. C.; Charlesworth, J. A.; Pussell, Bruce A.

doi:10.1111/j.1365-2249.1993.tb05956.x

Cited by 100 publications

(79 citation statements)

References 17 publications

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“…Though both UspA1 and UspA2 were found to be able to bind C3, a more dominant role was again observed for UspA2. Vitronectin is a regulatory component of the complement system that inhibits the terminal stages of the complement system by blocking membrane binding of C5b-7 and inhibition of C9 polymerization and eventually inhibiting formation of the MAC (97,134). UspA2 has been found to bind vitronectin (Fig.…”

Section: Complement Resistance and Major Ompsmentioning

confidence: 99%

Molecular Aspects ofMoraxella catarrhalisPathogenesis

Vries

Bootsma

Hays

et al. 2009

Microbiol Mol Biol Rev

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SUMMARY In recent years, Moraxella catarrhalis has established its position as an important human mucosal pathogen, no longer being regarded as just a commensal bacterium. Further, current research in the field has led to a better understanding of the molecular mechanisms involved in M. catarrhalis pathogenesis, including mechanisms associated with cellular adherence, target cell invasion, modulation of the host's immune response, and metabolism. Additionally, in order to be successful in the host, M. catarrhalis has to be able to interact and compete with the commensal flora and overcome stressful environmental conditions, such as nutrient limitation. In this review, we provide a timely overview of the current understanding of the molecular mechanisms associated with M. catarrhalis virulence and pathogenesis.

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Section: Complement Resistance and Major Ompsmentioning

confidence: 99%

Molecular Aspects ofMoraxella catarrhalisPathogenesis

Vries

Bootsma

Hays

et al. 2009

Microbiol Mol Biol Rev

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“…pathway of complement activation, the formation of the membrane attack complex (MAC), consisting of five components from C5b to C9 (Milis et al 1993, Su 1996, Singh et al 2010. It has been postulated that VT interacts with C5b-7 and forms a complex (VT-C5b-7) that cannot be introduced into the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Differentially expressed proteins in the blood serum of piglets in response to a diet supplemented with inulin

Herosimczyk¹,

Lepczyński²,

Ożgo³

et al. 2015

Polish Journal of Veterinary Sciences

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In the present study we introduced a two-dimensional electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry-based proteomic workflow to identify proteins that show altered expression as a result of the addition of 2% of water extract of inulin-type fructans to the diet of growing piglets. This analysis allowed us to detect an average of 240 spots per gel with a mass range from 10 to 250 kDa and a pH ranging from 3 to 10. Twenty protein spots were found to show statistically significant differences in their expression. Of these, 7 protein spots were up-regulated, whereas 13 showed down-regulation in response to the experimental diet. In total, 13 spots were identified, representing 8 distinct gene products. The experimental diet caused a significant change in proteins directly or indirectly involved in hemostasis and the innate immune response. Increased levels of fibrinogen along with decreased plasminogen expression may indicate that a fructan-rich diet favours the deposits of fibrin and promotes blood clotting. We also found increased expression of vitronectin and the alpha subunit of the complement component C8 which may protect the host organism against excessive cytolitic activity of the activated complement. The piglets from the experimental group had slightly increased values of IgG and IgA, whereas the IgM level tended to be decreased. The fructan-rich diet did not have any influence on plasma total cholesterol, HDL and LDL cholesterol and triglyceride levels.

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“…It consists of an N-ter-minal somatomedin-B domain (SMB), an RGD cell receptor binding site, four hemopexin (HPX)-like domains, and three heparin-binding domains (HBDs) (14). VN is a complement regulator that inhibits the formation of the membrane attack complex (MAC) by occupying the metastable membrane-binding site of the C5b7 complex and hindering its insertion into the cell membrane, thus preventing the completion of the C5b9 lytic pore (15). In addition, binding of C8 and C9 to the C5b7-VN complex leads to the formation of soluble C5b9 (SC5b9), which is hemolytically inactive.…”

mentioning

confidence: 99%

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Conde

Silva

Allonso

et al. 2016

J Virol

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Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV-infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system. IMPORTANCE Dengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV).The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly, NS1 itself also inhibited MAC activity, suggesting a direct role of this protein in the inhibition process. Our findings imply a role for NS1 as a terminal pathway inhibitor of the complement system. D engue constitutes a major public health problem in tropical and subtropical countries. According to current estimates, at least 390 million cases of dengue occur annually, of which approximately 100 million are symptomatic (1). The infection is caused by dengue virus (DENV), a member of the Flaviviridae family that cocirculates in nature as four distinct antigenic serotypes (DENV1 to -4). DENV infection in humans is generally asymptomatic, but symptomatic cases can vary from a mild and self-limited fever to a potentially fatal hemorrhagic syndrome (2). The DENV genome is composed of a single positive-sense RNA that encodes a single viral polyprotein that is further processed by viral and host proteases into three structural proteins (C, prM/M, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (3).NS1 ...

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Vitronectin-mediated inhibition of complement: evidence for different binding sites for C5b-7 and C9

Cited by 100 publications

References 17 publications

Molecular Aspects ofMoraxella catarrhalisPathogenesis

Molecular Aspects ofMoraxella catarrhalisPathogenesis

Differentially expressed proteins in the blood serum of piglets in response to a diet supplemented with inulin

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

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