Cell Surface-Binding Motifs of L2 That Facilitate Papillomavirus Infection

Yang, Rongcun; Day, Patricia M.; Yutzy, William H.; Lin, Ken Y.; Hung, Chien Fu; Roden, Richard B.S.

doi:10.1128/jvi.77.6.3531-3541.2003

Cited by 89 publications

(97 citation statements)

References 54 publications

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“…The prolonged exposure on the cell surface was partially explained by the putative involvement of a secondary receptor protein responsible for the uptake of virions (18,39). Indeed, recent reports suggest that the minor capsid protein L2 may bind to a cell surface protein(s) other than HSPGs (24,48). In line with this, the classical receptor-and clathrin-dependent endocytic pathway has been demonstrated to be essential for papillomavirus infection (6,13,39).…”

Section: Discussionmentioning

confidence: 50%

Further Evidence that Papillomavirus Capsids Exist inTwo DistinctConformations

Selinka

Giroglou

Nowak

et al. 2003

J Virol

117

115

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Cell surface heparan sulfate proteoglycans (HSPGs) serve as primary attachment receptors for human papillomaviruses (HPVs). To demonstrate that a biologically functional HPV-receptor interaction is restricted to a specific subset of HSPGs, we first explored the role of HSPG glucosaminoglycan side chain modifications. We demonstrate that HSPG O sulfation is essential for HPV binding and infection, whereas de-N-sulfated heparin interfered with VLP binding but not with HPV pseudoinfection. This points to differences in VLP-HSPG and pseudovirion-HSPG interactions. Interestingly, internalization kinetics of VLPs and pseudovirions, as measured by fluorescence-activated cell sorting analysis, also differ significantly with approximate half times of 3.5 and 7.5 h, respectively. These data suggest that differences in HSPG binding significantly influence postbinding events. We also present evidence that pseudovirions undergo a conformational change after cell attachment. A monoclonal antibody (H33.J3), which displays negligible effectiveness in preattachment neutralization assays, efficiently neutralizes cell-bound virions. However, no difference in H33.J3 binding to pseudovirions and VLPs was observed in enzyme-linked immunosorbent assay and virus capture assays. In contrast to antibody H33.B6, which displays equal efficiencies in pre-and postattachment neutralization assays, H33.J3 does not block VLP binding to heparin, demonstrating that it interferes with steps subsequent to virus binding. Our data strongly suggest that H33.J3 recognizes a conformation-dependent epitope in capsid protein L1, which undergoes a structural change after cell attachment.Human papillomaviruses (HPVs) are highly species-specific epitheliotropic DNA viruses. Of the more than 100 different genotypes, HPV type 16 (HPV16), HPV18, HPV31, HPV33, HPV35, HPV45, and HPV58 are most closely associated with cervical epithelial neoplasias and members of the group of HPV imposing a "high risk" for malignant progression to invasive genital carcinomas (30). The nonenveloped papillomavirus is composed of 360 copies of the major capsid protein L1, organized in 72 capsomeres, and probably 12 copies of the minor capsid protein L2 (1, 43). The encapsidated genome is an 8,000-bp circularized double-stranded DNA associated with cellular histones.Despite their considerable clinical significance, the initial steps leading to infection with these viruses, as well as the mechanisms involved in virus entry into host cells, have not yet been completely elucidated due to the limited growth properties of HPV in cell cultures and the ubiquitous expression of HPV-binding proteins. The use of virus-like particles (VLPs) (20,25,36,46,49) has helped in the study of the initial interaction of papillomavirus particles with cell surfaces. It was established that VLPs of many HPV types compete for binding to the same highly conserved proteinaceous attachment receptor. In contrast to L1, L2 protein was not essential for binding, since L1 VLPs bound as efficiently as L1L2 VLPs (32,3...

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Section: Discussionmentioning

confidence: 50%

Further Evidence that Papillomavirus Capsids Exist inTwo DistinctConformations

Selinka

Giroglou

Nowak

et al. 2003

J Virol

117

115

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“…This concept of a specific L2 receptor is supported by several studies examining L2-mediated infectivity (11,12). Kawana et al (11) demonstrated that preincubation of COS-1 cells with the HPV16 L2 peptide aa 108 -120 decreased infectivity of HPV16 pseudovirions.…”

Section: Discussionmentioning

confidence: 56%

“…Kawana et al (11) demonstrated that preincubation of COS-1 cells with the HPV16 L2 peptide aa 108 -120 decreased infectivity of HPV16 pseudovirions. Additionally, Yang et al (12) suggested that HPV16L1L2 VLP binding to the cell surface of HeLa cells causes aa 13-31 of the L2 protein to be displayed on the virion surface, interact with a secondary receptor, and facilitate infection. The existence of an L2-specific receptor becomes highly conceivable when these studies are viewed in the context of our results.…”

Section: Discussionmentioning

confidence: 99%

“…Collectively, these interactions imply a significant role for L2 in the formation of the virion. Furthermore, L2 facilitates HPV infection through an interaction between the N terminus region of the L2 protein and an unknown cell surface receptor (11,12). Further functions of L2 include binding of the virion to the cytoskeleton, transport within the cytoplasm (13), and facilitation of endosomal escape of the viral genome after infection (14).…”

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confidence: 99%

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A Major Role for the Minor Capsid Protein of Human Papillomavirus Type 16 in Immune Escape

Fahey¹,

Raff²,

Silva

et al. 2009

The Journal of Immunology

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High-risk human papillomavirus (HPV) infection of the cervical epithelium is causally linked with the generation of cervical cancer. HPV does not activate Langerhans cells (LC), the APC at the site of infection, leading to immune evasion. The HPV protein responsible for inducing this immune escape has not been determined. We demonstrate that LC exposed to the minor capsid protein L2 in HPV16L1L2 virus-like particles do not phenotypically or functionally mature. However, HPV16L1 virus-like particles significantly induce activation of LC. Our data suggest that the L2 protein plays a specific role in the induction of this immune escape of HPV16 through the manipulation of LC. This novel function is the first immune modulating action attributed to the L2 protein and adds significantly to our understanding of the mechanism of HPV immune escape.

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“…pGEX-6P-GFP was generated by ligation of pGEX-6P-1 with green fluorescent protein (GFP; Pharmacia) from pGL-2 (Clontech) between EcoRI and SalI. The SOCS3 gene cloned from mouse monocyte cell line RAW264.7 was subcloned into plasmid pGEX-6P-GFP to generate glutathione S-transferase (GST)-SOCS3-GFP or GST-GFP fusion protein using our previously described methods (21,22). GST-SOCS3-GFP was bound to a GST Trap FF column, and detergent extracts of 2 Â 10 6 DCs in buffer A were passed over the column.…”

Section: Introductionmentioning

confidence: 99%

Tumor-Induced Suppressor of Cytokine Signaling 3 Inhibits Toll-like Receptor 3 Signaling in Dendritic Cells via Binding to Tyrosine Kinase 2

Zeng

Liu

et al. 2008

Cancer Research

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The suppressor of cytokine signaling (SOCS) family of negative regulatory proteins is up-regulated in response to several cytokines and pathogen-associated molecular patterns (PAMP) and suppresses cellular signaling responses by binding receptor phosphotyrosine residues. Exposure of bone marrow-derived dendritic cells (BMDC) to 1D8 cells, a murine model of ovarian carcinoma, suppresses their ability to express CD40 and stimulate antigen-specific responses in response to PAMPs and, in particular, to polyinosinic acid:poly-CMP (polyI:C) with the up-regulated SOCS3 transcript and protein levels. The ectopic expression of SOCS3 in both the macrophage cell line RAW264.7 and BMDCs decreased signaling in response to both polyI:C and IFNA. Further, knockdown of SOCS3 transcripts significantly enhanced the responses of RAW264.7 and BMDCs to both polyI:C and IFNA. Immunoprecipitation and pull-down studies show that SOCS3 binds to the IFNA receptor tyrosine kinase 2 (TYK2). Because polyI:C triggers autocrine IFNA signaling, binding of SOCS3 to TYK2 may thereby suppress the activation of BMDCs by polyI:C and IFNA. Thus, elevated levels of SOCS3 in tumor-associated DCs may potentially resist the signals induced by Toll-like receptor 3 ligands and type I IFN to decrease DC activation via binding with IFNA receptor TYK2.

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Cell Surface-Binding Motifs of L2 That Facilitate Papillomavirus Infection

Cited by 89 publications

References 54 publications

Further Evidence that Papillomavirus Capsids Exist inTwo DistinctConformations

Further Evidence that Papillomavirus Capsids Exist inTwo DistinctConformations

A Major Role for the Minor Capsid Protein of Human Papillomavirus Type 16 in Immune Escape

Tumor-Induced Suppressor of Cytokine Signaling 3 Inhibits Toll-like Receptor 3 Signaling in Dendritic Cells via Binding to Tyrosine Kinase 2

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