Nuclear import and DNA binding of human papillomavirus type 45 L1 capsid protein

Nelson, Lisa M.; Rose, Robert C.; Roux, Lucia Le; Lane, Christophore; Bruya, Kate; Moroianu, Junona

doi:10.1002/1097-4644(20001101)79:2<225::aid-jcb60>3.3.co;2-1

Cited by 4 publications

(4 citation statements)

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“…In accordance with this finding, linear L1 epitopes are continuously detected in Lamp-3 positive compartments late in infection [60]. Previous studies showing that intact HPV capsids exceed the size capacity for transit across the central nuclear pore complex channel had already suggested that disassembly of the viral particle must occur before nuclear import [73,74]. L2 protein is not essential for viral uncoating, as measured by the detection of bromodeoxyuridine-labeled genome after infection with L1-only particles [70].…”

Section: Viral Uncoating and Egress From Endosomessupporting

confidence: 77%

Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleus

2009

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Papillomaviruses are epitheliotropic non-enveloped double stranded DNA viruses, whose replication is strictly dependent on the terminally differentiating tissue of the epidermis. They induce self-limiting benign tumors of skin and mucosa, which may progress to malignancy like cervical carcinoma. Prior to entry into basal cells, virions attach to heparan sulfate moieties of the basement membrane. This triggers conformational changes, which affect both capsid proteins, L1 and L2, and which are a prerequisite for interaction with the elusive uptake receptor. These processes are very slow resulting in an uptake halftime of up to 14 h. This review summarizes recent advances in our understanding of cell surface events, internalization and subsequent intracellular trafficking of Papillomaviruses. Introductory remarksPapillomaviruses (PV) are epitheliotropic nonenveloped small DNA viruses with icosahedral symmetry. Their strict dependence on terminally differentiating keratinocytes for completion of the replication cycle initially made the study of entry processes difficult with regard to two aspects. First, it was impossible to produce virions until the development of organotypic raft cultures based on keratinocytes harboring human papillomavirus (HPV) genomes [1]. Since these culture systems produced only very limited amounts of virions they provided only a partial relief. The limitation was partially overcome by the use of DNA-free virus-like particles and later by pseudovirions harboring marker plasmids, which were generated using heterologous expression systems [2][3][4]. The observation that codon optimization of capsid genes yielded high level expression of capsid proteins [5,6] and the development of packaging cell lines harboring high copy numbers of packaging plasmids finally allowed large scale productions of pseudovirions [7] as well as quasivirions [8]. This advance further facilitated the investigation of early events of PV infection. Second, until very recently [9], it was not possible to infect either organotypic raft cultures or primary keratinocytes in vitro unless pseudovirions had been activated (see below) [10]. The reason for this deficiency is unknown but suggests that taking primary keratinocytes into culture induces enough changes to make them refractory to HPV infection. Therefore, researchers have had to rely on established cell lines, the most commonly used of which is the HaCaT cell line, to study PV binding and uptake. However, the recent development of an in vivo mouse model by the Schiller group will allow for the testing of observations made in vitro. In this review we will focus on the entry of HPV type 16 (HPV16) and closely related viruses, which are the main cause of various cancers including cervical carcinoma. In vitro data backed by recent in vivo studies suggest an elaborate sequence of cell surface events Capsid structureTo fully appreciate viral entry strategies we have to discuss their surface structure. The outer shell of PV is composed of 360 molecules of the major ...

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Section: Viral Uncoating and Egress From Endosomessupporting

confidence: 77%

Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleus

2009

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“…KPNA2 plays a crucial role during viral infections mainly by importing parts of the viral machinery to the nucleus. It has so far been implicated in the shuttling of factors from a variety of viruses such as HIV [76], Epstein-Barr virus [77], polyomavirus [78] and HPV [79][80][81]. Furthermore, KPNA2 has been proposed to hold a role in regulating viral capsid assembly, preventing it from faultily occurring in the cytoplasm [82].…”

Section: Kpna2 Has Been Implicated In a Multitude Of Cellular Processesmentioning

confidence: 99%

The functional role of the novel biomarker karyopherin α 2 (KPNA2) in cancer

2013

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In recent years, Karyopherin α 2 (KPNA2) has emerged as a potential biomarker in multiple cancer forms. The aberrant high levels observed in cancer tissue have been associated with adverse patient characteristics, prompting the idea that KPNA2 plays a role in carcinogenesis. This notion is supported by studies in cancer cells, where KPNA2 deregulation has been demonstrated to affect malignant transformation. By virtue of its role in nucleocytoplasmic transport, KPNA2 is implicated in the translocation of several cancer-associated proteins. We provide an overview of the clinical studies that have established the biomarker potential of KPNA2 and describe its functional role with an emphasis on established associations with cancer.

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“…For example, parvovirus delivers its DNA into the nucleus through karyopherin ␣ and karyopherin ␤ (17). The replication of human papillomavirus is inhibited by antibodies against KPNA2 and KPNB1 (18). Moreover, herpesvirus and adenovirus rely on karyopherins for their nuclear entry (19).…”

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confidence: 99%

Karyopherin Alpha 6 Is Required for Replication of Porcine Reproductive and Respiratory Syndrome Virus and Zika Virus

Yang

Wang

Yang

et al. 2018

J Virol

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Movement of macromolecules between the cytoplasm and the nucleus occurs through the nuclear pore complex (NPC). Karyopherins comprise a family of soluble transport factors facilitating the nucleocytoplasmic translocation of proteins through the NPC. In this study, we found that karyopherin α6 (KPNA6; also known as importin α7) was required for the optimal replication of porcine reproductive and respiratory syndrome virus (PRRSV) and Zika virus (ZIKV), which are positive-sense, single-stranded RNA viruses replicating in the cytoplasm. The KPNA6 protein level in virus-infected cells was much higher than that in mock-infected controls, whereas the KPNA6 transcript remains stable. Viral infection blocked the ubiquitin-proteasomal degradation of KPNA6, which led to an extension of the KPNA6 half-life and the elevation of the KPNA6 level in comparison to mock-infected cells. PRRSV nsp12 protein induced KPNA6 stabilization. KPNA6 silencing was detrimental to the replication of PRRSV, and KPNA6 knockout impaired ZIKV replication. Moreover, KPNA6 knockout blocked the nuclear translocation of PRRSV nsp1β but had a minimal effect on two other PRRSV proteins with nuclear localization. Exogenous restitution of KPNA6 expression in the KPNA6-knockout cells results in restoration of the nuclear translocation of PRRSV nsp1β and the replication of ZIKV. These results indicate that KPNA6 is an important cellular factor for the replication of PRRSV and ZIKV. Positive-sense, single-stranded RNA (+ssRNA) viruses replicate in the cytoplasm of infected cells. The roles of transport factors in the nucleocytoplasmic trafficking system for the replication of +ssRNA viruses are not known. In this study, we discovered that PRRSV and ZIKV viruses needed karyopherin α6 (KPNA6), one of the transport factors, to enhance the virus replication. Our data showed that viral infection induced an elevation of the KPNA6 protein level due to an extension of the KPNA6 half-life via viral interference of the ubiquitin-proteasomal degradation of KPNA6. Notably, KPNA6 silencing or knockout dramatically reduced the replication of PRRSV and ZIKV. PRRSV nsp1β depended on KPNA6 to translocate into the nucleus. In addition, exogenous restitution of KPNA6 expression in KPNA6-knockout cells led to the restoration of nsp1β nuclear translocation and ZIKV replication. These results reveal a new aspect in the virus-cell interaction and may facilitate the development of novel antiviral therapeutics.

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Nuclear import and DNA binding of human papillomavirus type 45 L1 capsid protein

Cited by 4 publications

References 0 publications

Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleus

Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleus

The functional role of the novel biomarker karyopherin α 2 (KPNA2) in cancer

Karyopherin Alpha 6 Is Required for Replication of Porcine Reproductive and Respiratory Syndrome Virus and Zika Virus

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