Human Papillomavirus Species-Specific Interaction with the Basement Membrane-Resident Non-Heparan Sulfate Receptor

Richards, Kathleen F.; Mukherjee, Santanu; Bienkowska-Haba, Malgorzata; Pang, Jia; Sapp, Martin

doi:10.3390/v6124856

Cited by 25 publications

(34 citation statements)

References 76 publications

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“…However, the cleavage appeared to be inefficient unless the virus was preincubated with heparin. Since the interaction of HPV16 PsV with highly sulfated HS facilitates infection by induction of a conformational change in virions (19,70), it is likely that this conformational change exposed a protease consensus sequence of L1 that was at least partially obscured in the incoming HPV16 PsV.…”

Section: Discussionmentioning

confidence: 99%

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

Cerqueira

Ventayol

Vogeley

et al. 2015

J Virol

104

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The entry of human papillomaviruses into host cells is a complex process. It involves conformational changes at the cell surface, receptor switching, internalization by a novel endocytic mechanism, uncoating in endosomes, trafficking of a subviral complex to the Golgi complex, and nuclear entry during mitosis. Here, we addressed how the stabilizing contacts in the capsid of human papillomavirus 16 (HPV16) may be reversed to allow uncoating of the viral genome. Using biochemical and cell-biological analyses, we determined that the major capsid protein L1 underwent proteolytic cleavage during entry. In addition to a dispensable cathepsin-mediated proteolysis that occurred likely after removal of capsomers from the subviral complex in endosomes, at least two further proteolytic cleavages of L1 were observed, one of which was independent of the low-pH environment of endosomes. This cleavage occurred extracellularly. Further analysis showed that the responsible protease was the secreted trypsin-like serine protease kallikrein-8 (KLK8) involved in epidermal homeostasis and wound healing. Required for infection, the cleavage was facilitated by prior interaction of viral particles with heparan sulfate proteoglycans. KLK8-mediated cleavage was crucial for further conformational changes exposing an important epitope of the minor capsid protein L2. Occurring independently of cyclophilins and of furin that mediate L2 exposure, KLK8-mediated cleavage of L1 likely facilitated access to L2, located in the capsid lumen, and potentially uncoating. Since HPV6 and HPV18 also required KLK8 for entry, we propose that the KLK8-dependent entry step is conserved. IMPORTANCEOur analysis of the proteolytic processing of incoming HPV16, an etiological agent of cervical cancer, demonstrated that the capsid is cleaved extracellularly by a serine protease active during wound healing and that this cleavage was crucial for infection. The cleavage of L1 is one of at least four structural alterations that prime the virus extracellularly for receptor switching, internalization, and possibly uncoating. This step was also important for HPV6 and HPV18, which may suggest that it is conserved among the papillomaviruses. This study advances the understanding of how HPV16 initially infects cells, strengthens the notion that wounding facilitates infection of epidermal tissue, and may help the development of antiviral measures. Human papillomaviruses (HPVs) comprise a large family of small, nonenveloped DNA viruses with transforming potential. HPVs selectively infect basal keratinocytes of stratified skin and mucosal epithelia and persist, mostly without clinical symptoms, in virtually every part of the human skin. The biological costs of HPV persistence range from benign papilloma and genital warts over preneoplastic lesions to anogenital or oropharyngeal cancers (1). In fact, infection by the so-called "high-risk" HPV causes about 5% of all human cancers (2). Of these, cervical cancers are the most prevalent. However, HPV-associated oropharyngea...

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Section: Discussionmentioning

confidence: 99%

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

Cerqueira

Ventayol

Vogeley

et al. 2015

J Virol

104

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“…4E), did not completely abolish the binding of AGMA1 to the cells (leaving 50% of binding unaffected), suggesting that other surface receptors, as yet unidentified, may be able to interact with the polymer. Of note, beside HSPGs, other cell receptors have been identified that contribute to HPV infection, including ␣6␤4 integrin (36) and annexin A2 (37), and some reports even suggest the possibility that HPV infection occurs in a HSPG-independent manner (38,39). Interestingly, the levels of cell surface expression of HSPGs (40) and of heparinase (41) can vary during inflammation, which is normally triggered by viral infections, suggesting the possibility that, depending on the pathological setting, HSPGs or other (as yet unidentified) HPV receptors may contribute differently to HPV infection.…”

Section: Discussionmentioning

confidence: 99%

The Agmatine-Containing Poly(Amidoamine) Polymer AGMA1 Binds Cell Surface Heparan Sulfates and Prevents Attachment of Mucosal Human Papillomaviruses

Cagno

Donalisio

Bugatti

et al. 2015

Antimicrob Agents Chemother

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The agmatine-containing poly(amidoamine) polymer AGMA1 was recently shown to inhibit the infectivity of several viruses, including human papillomavirus 16 (HPV-16), that exploit cell surface heparan sulfate proteoglycans (HSPGs) as attachment receptors. The aim of this work was to assess the antiviral activity of AGMA1 and its spectrum of activity against a panel of lowrisk and high-risk HPVs and to elucidate its mechanism of action. AGMA1 was found to be a potent inhibitor of mucosal HPV types (i.e., types 16, 31, 45, and 6) in pseudovirus-based neutralization assays. The 50% inhibitory concentration was between 0.34 g/ml and 0.73 g/ml, and no evidence of cytotoxicity was observed. AGMA1 interacted with immobilized heparin and with cellular heparan sulfates, exerting its antiviral action by preventing virus attachment to the cell surface. The findings from this study indicate that AGMA1 is a leading candidate compound for further development as an active ingredient of a topical microbicide against HPV and other sexually transmitted viral infections. Human papillomaviruses (HPVs) are members of the Papillomaviridae family of double-stranded DNA nonenveloped viruses (1). The 8-kb HPV genome is enclosed in a capsid shell comprising major (L1) and minor (L2) structural proteins. Most of the HPVs belonging to the Alphapapillomavirus genus are sexually transmitted and infect the anogenital mucosa. For the great majority of immunocompetent individuals, HPV infections are transient, causing asymptomatic epithelial infections or benign epithelial hyperplasia. Genital warts are the most common lesions, caused mainly by HPV-6 and HPV-11. Small proportions of men and women fail to control viral infections and develop HPV-related malignancies, including carcinoma of the cervix, vulva, vagina, penis, anus, or oropharynx. Several HPV types belonging to HPV species 7 (HPV-18, HPV-39, HPV-45, HPV-59, and HPV-68) or species 9 (HPV-16, HPV-31, HPV-33, HPV-35, HPV-52, HPV-58, and HPV-67) can confer high oncogenic risk. HPV-16 and HPV-18 cause about 70% of all cases of invasive cervical cancer worldwide (followed by HPV-31, HPV-33, and HPV-45) (2).It has been estimated that more than 528,000 new cases of cervical cancer occur every year, and cervical cancer caused 266,000 deaths worldwide in 2012 (3, 4). Eighty-five percent of cervical cancer cases occur in women living in low-socioeconomic settings, primarily due to a lack of access to effective cervical cancer screening programs. No anti-HPV drugs are available to cure HPV lesions; therefore, the current treatments are ablative and directed at the abnormal cells associated with HPV, rather than at the virus itself. The development of new ways to prevent genital infections is essential in order to reduce the burden of HPV diseases. Two prophylactic vaccines, Gardasil and Cervarix, are currently available. The first is designed to protect against oncogenic HPV types 16 and 18 and low-risk HPV types 6 and 11 and therefore is preventive against both cancer and genital warts (5); the ...

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“…HPV are epitheliotropic viruses whose replication cycle is strictly dependent on the terminal differentiation process of keratinocytes of the skin and mucosa (Doorbar et al, 2015). To achieve entry, HPV preferentially binds to components of the basement membrane, which separates the epidermal from the dermal tissue (Culp et al, 2006a;Selinka et al, 2007;Richards et al, 2014). Animal models have revealed that access to the basement membrane requires disruption of the epidermal architecture such as wounds, abrasions or microlesions (Roberts et al, 2007).…”

Section: Hpv Is Delivered Into the Nucleus In A Transport Vesiclementioning

confidence: 99%

The Role of Promyelocytic Leukemia Nuclear Bodies During HPV Infection

Guion

Sapp

2020

Front. Cell. Infect. Microbiol.

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Promyelocytic leukemia (PML) nuclear bodies (NBs) are highly dynamic subnuclear structures. Their name giving major component, PML protein, is essential for their formation. PML is present in many different isoforms due to differential splicing, which seem to contribute differently to PML NBs function. Sp100 and DAXX are also permanently residing in these structures. PML NBs disassemble in mitosis to form large cytoplasmic aggregates and reassemble after completion of cell division. Posttranslational modifications such as SUMOylation play important roles for protein association with PML NBs. In addition to the factors permanently associated with PML NBs, a large number of proteins may transiently reside in PML NBs dependent on cell stage, type, and condition. PML NBs have been indirectly implicated in a large number of cellular processes including apoptosis, transcriptional regulation, DNA repair and replication. They are considered hot spots for posttranslational modifications and may serve as readily accessible protein depots. However, a precise function has been difficult to assign. Many DNA viruses target PML NBs after entry often resulting in reorganization of these subnuclear structures. Antiviral activity has been assigned to PML NBs partially based on the observation that PML protein is an interferon stimulated gene. In contrast, human papillomavirus (HPV) infection requires the presence of PML protein suggesting that PML NBs may be essential to establish infection. This review will summarize and discuss recent advances in our understanding of the role of PML NBs and individual protein components in the establishment of HPV infection.

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Human Papillomavirus Species-Specific Interaction with the Basement Membrane-Resident Non-Heparan Sulfate Receptor

Cited by 25 publications

References 76 publications

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

The Agmatine-Containing Poly(Amidoamine) Polymer AGMA1 Binds Cell Surface Heparan Sulfates and Prevents Attachment of Mucosal Human Papillomaviruses

The Role of Promyelocytic Leukemia Nuclear Bodies During HPV Infection

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