Species-specific differences in the structure of orthopoxvirus complement-binding protein

Уварова, Е. А.; Щелкунов, С. Н.

doi:10.1016/s0168-1702(01)00332-x

Cited by 28 publications

(28 citation statements)

References 30 publications

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“…Vaccinia complement control protein (VCP) was the first described and is the most completely characterized (21)(22)(23)(24)(25)(26). Other poxviruses that retain homologues to VCP in their genome include variola virus (small pox), cowpox, and monkeypox, the latter missing the fourth CCP domain and perhaps not functional (27)(28)(29)(30). With the exception of Herpes Simplex virus type 1, which encodes glycoprotein C, a complement regulator that does not have homology to any known inhibitor, all herpesviruses that encode complement regulators belong to the rhadinovirus genus.…”

Section: Discussionmentioning

confidence: 99%

Functional Activity of the Complement Regulator Encoded by Kaposi's Sarcoma-associated Herpesvirus

Spiller¹,

Blackbourn²,

Mark³

et al. 2003

Journal of Biological Chemistry

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Kaposi's sarcoma-associated herpesvirus (KSHV) is closely associated with Kaposi's sarcoma and certain B-cell lymphomas. The fourth open reading frame of the KSHV genome encodes a protein (KSHV complement control protein (KCP, previously termed ORF4)) predicted to have complement-regulating activity. Here, we show that soluble KCP strongly enhanced the decay of classical C3-convertase but not the alternative pathway C3-convertase, when compared with the host complement regulators: factor H, C4b-binding protein, and decay-accelerating factor. The equilibrium affinity constant (K D ) of KCP for C3b and C4b was determined by surface plasmon resonance analysis to range between 0.47-10 M and 0.025-6.1 M, respectively, depending on NaCl concentration and cation presence. Soluble and cell-associated KCP acted as a cofactor for factor I (FI)-mediated cleavage of both C4b and C3b and induced the cleavage products C4d and iC3b, respectively. In the presence of KCP, FI further cleaved iC3b to C3d, which has never been described before as complement receptor 1 only mediates the production of C3dg by FI. KCP would enhance virus pathogenesis through evading complement attack, opsonization, and anaphylaxis but may also aid in targeting KSHV to one of its host reservoirs since C3d is a ligand for complement receptor 2 on B-cells.Kaposi's sarcoma-associated herpesvirus (KSHV) 1 is the likely etiologic agent of Kaposi's sarcoma and is the most recently identified member of the human Herpesviridae family (1, 2). KSHV is also associated with the B-cell tumors body cavitybased primary effusion lymphomas and the plasma cell variant of multicentric Castleman's Disease (for reviews, see Refs. 3 and 4). KSHV belongs to the rhadinovirus genus of the Gammaherpesvirinae subfamily, the prototype of which is Herpesvirus saimiri (HVS). The long unique region of the KSHV genome comprises 140.5 kb and contains over 80 open reading frames (ORFs) (5). Several of the ORFs encode host cell homologues (e.g. viral cyclin D, viral interleukin-8 G protein-coupled receptor, and a bcl-2 homologue) with the potential to regulate the cell cycle and the immune response thereby contributing to the virulence and the pathogenesis of KSHV (5,6).The fourth open reading frame, ORF4, was initially speculated to have complement regulatory abilities based on its homology to human complement regulators decay-accelerating factor (DAF) and membrane cofactor and to previously described virus-encoded complement inhibitors (5). The KSHV ORF4 gene is predicted to encode a KCP protein of 550 amino acids (data base reference SPTREMBL:O40912), and the first 280 amino acids are predicted to encode four complement control protein (CCP) domains. CCP domains are defined by a consensus sequence of ϳ60 amino acids containing four invariant cysteine residues that form disulfide links, which results in the CCP forming a globular domain with a hydrophobic core enclosed by ␤-strands (7,8). While the CCP domain is not exclusive to complement control proteins, all but one of the C3-co...

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Section: Discussionmentioning

confidence: 99%

Functional Activity of the Complement Regulator Encoded by Kaposi's Sarcoma-associated Herpesvirus

Spiller¹,

Blackbourn²,

Mark³

et al. 2003

Journal of Biological Chemistry

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“…The prototypical poxviral complement regulatory protein is the VV complement control protein (VCP) (47). Additional VCP-like orthologs have been detected in other poxviruses such as MPV, variola virus (VarV), and CPV (61,107). VCP is a highly stable monomeric secreted protein (94) that inhibits both the classical and alternative complement activation pathways by directly and indirectly promoting the decay of the C3 convertase (46,79).…”

Section: Viromimicry: Virokines and Viroreceptorsmentioning

confidence: 99%

Poxvirus Immunomodulatory Strategies: Current Perspectives

Johnston

McFadden

2003

J Virol

150

103

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“…The vaccinia virus (VACV) complement control protein (VCP) is the most thoroughly studied poxvirus complement-regulatory protein. It is homologous to the smallpox inhibitor of complement enzymes (SPICE) encoded by variola virus and to the monkeypox inhibitor of complement enzymes (MoPICE) (19,33,36,41). VCP and SPICE inhibit the activation of the classical and alternative complement pathways by accelerating the irreversible decay of C3 and C5 convertases and by functioning as cofactors for the factor I-mediated cleavage and inactivation of C3b and C4b (3,17,22,26,(32)(33)(34)36).…”

mentioning

confidence: 99%

Cell Surface Expression of the Vaccinia Virus Complement Control Protein Is Mediated by Interaction with the Viral A56 Protein and Protects Infected Cells from Complement Attack

Girgis

DeHaven

Fan

et al. 2008

J Virol

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The vaccinia virus (VACV) complement control protein (VCP) is the major protein secreted from VACVinfected cells. It has been reported that VCP binds to the surfaces of uninfected cells by interacting with heparan sulfate proteoglycans (HSPGs). In this study, we show that VCP is also expressed on the surfaces of infected cells and demonstrate that surface localization occurs independently of HSPGs. Since VCP does not contain a transmembrane domain, we hypothesized that VCP interacts with a membrane protein that localizes to the infected-cell surface. We show that the VACV A56 membrane protein is necessary for the cell surface expression of VCP and demonstrate that VCP and A56 interact in VACV-infected cells. Since the surface expression of VCP was abrogated by reducing agents, we examined the contribution of an unpaired cysteine residue on VCP to VCP surface expression and VCP's interaction with A56. To do this, we mutated the unpaired cysteine in VCP and generated a recombinant virus expressing the altered form of VCP. Following the infection of cells with the mutant virus, VCP was neither expressed on the cell surface nor able to interact with A56. Importantly, the cell surface expression of VCP was found to protect infected cells from complementmediated lysis. Our findings suggest a new function for VCP that may be important for poxvirus pathogenesis and impact immune responses to VACV-based vaccines.The complement system is composed of ϳ30 soluble and cell surface proteins that work in concert to protect the host from invading pathogens (reviewed in references 46 and 47). Complement can become activated by multiple pathways that converge on the formation of a C3 convertase, the proteolytic complex responsible for cleaving the central complement component, C3. Cleavage of C3 results in the production of the anaphylatoxin C3a and the opsonic fragment C3b. The generation of C3b results in the formation of a C5 convertase, the proteolytic complex responsible for cleaving C5 into the C5a anaphylatoxin and C5b. C5b, in turn, nucleates the formation of a lytic pore called the membrane attack complex.

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Species-specific differences in the structure of orthopoxvirus complement-binding protein

Cited by 28 publications

References 30 publications

Functional Activity of the Complement Regulator Encoded by Kaposi's Sarcoma-associated Herpesvirus

Functional Activity of the Complement Regulator Encoded by Kaposi's Sarcoma-associated Herpesvirus

Poxvirus Immunomodulatory Strategies: Current Perspectives

Cell Surface Expression of the Vaccinia Virus Complement Control Protein Is Mediated by Interaction with the Viral A56 Protein and Protects Infected Cells from Complement Attack

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