Papillomaviruses and Endocytic Trafficking

Siddiqa, Abida; Broniarczyk, Justyna; Banks, Lawrence

doi:10.3390/ijms19092619

Cited by 37 publications

(49 citation statements)

References 205 publications

(256 reference statements)

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“…L1 shows nuclear localization in HaCaT keratinocytes and in the murine genital tract model. HeLa cells have been utilized for many HPV entry studies and have provided the foundation for many recent advances (8,29,30). Comparative analyses of HPV trafficking in HeLa and the normal human keratinocyte cell line HaCaT have revealed no differences (31)(32)(33)(34).…”

Section: Fig 2 L1mentioning

confidence: 99%

Human Papillomavirus 16 Capsids Mediate Nuclear Entry during Infection

Day¹,

Weisberg

Thompson³

et al. 2019

J Virol

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Infectious human papillomavirus 16 (HPV16) L1/L2 pseudovirions were found to remain largely intact during vesicular transport to the nucleus. By electron microscopy, capsids with a diameter of 50 nm were clearly visible within small vesicles attached to mitotic chromosomes and to a lesser extent within interphase nuclei, implying nuclear disassembly. By confocal analysis, it was determined that nuclear entry of assembled L1 is dependent upon the presence of the minor capsid protein, L2, but independent of encapsidated DNA. We also demonstrate that L1 nuclear localization and mitotic chromosome association can occur in vivo in the murine cervicovaginal challenge model of HPV16 infection. These findings challenge the prevailing concepts of PV uncoating and disassembly. More generally, they document that a largely intact viral capsid can enter the nucleus within a transport vesicle, establishing a novel mechanism by which a virus accesses the nuclear cellular machinery. IMPORTANCE Papillomaviruses (PVs) comprise a large family of nonenveloped DNA viruses that include HPV16, among other oncogenic types, the causative agents of cervical cancer. Delivery of the viral DNA into the host cell nucleus is necessary for establishment of infection. This was thought to occur via a subviral complex following uncoating of the larger viral capsid. In this study, we demonstrate that little disassembly of the PV capsid occurs prior to nuclear delivery. These surprising data reveal a previously unrecognized viral strategy to access the nuclear replication machinery. Understanding viral entry mechanisms not only increases our appreciation of basic cell biological pathways but also may lead to more effective antiviral interventions.

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Section: Fig 2 L1mentioning

confidence: 99%

Human Papillomavirus 16 Capsids Mediate Nuclear Entry during Infection

Day¹,

Weisberg

Thompson³

et al. 2019

J Virol

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“…HPV infectious entry involves a complex series of steps, including the attachment of virus to the extracellular matrix, the structural remodelling of the virion, receptor attachment, endocytic uptake, intracellular trafficking through the endosomal compartment, uncoating, and the recruitment of different components of the cellular transport machinery to ensure delivery of the incoming viral genomes to the nucleus through the trans-Golgi network (25)(26)(27). However, no studies have been performed to investigate whether potential phosphorylation of the HPV capsid proteins can play any roles in any of these processes.…”

Section: Discussionmentioning

confidence: 99%

“…Interactions of the viral capsid proteins with cellular components play an important role in papillomavirus infectious entry (25)(26)(27). Intracellular processing of the viral capsid is dependent on a number of different host factors, such as furin (13), cyclophilin (16), and gamma-secretase (21,(28)(29)(30), among others.…”

mentioning

confidence: 99%

Phosphorylation of Human Papillomavirus Type 16 L2 Contributes to Efficient Virus Infectious Entry

Broniarczyk

Massimi

Pim

et al. 2019

J Virol

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The human papillomavirus (HPV) capsid comprises two viral proteins, L1 and L2, with the L2 component being essential to ensure efficient endocytic transport of incoming viral genomes. Several studies have previously reported that L1 and L2 are posttranslationally modified, but it is uncertain whether these modifications affect HPV infectious entry. Using a proteomic screen, we identified a highly conserved phospho-acceptor site on the HPV-16 and bovine papillomavirus 1 (BPV-1) L2 proteins. The phospho-modification of L2 and its presence in HPV pseudovirions (PsVs) were confirmed using anti-phospho-L2-specific antibodies. Mutation of the phosphoacceptor sites of both HPV-16 and BPV-1 L2 resulted in the production of infectious virus particles, with no differences in efficiencies of packaging the reporter DNA. However, these mutated PsVs showed marked defects in infectious entry. Further analysis revealed a defect in uncoating, characterized by a delay in the exposure of a conformational epitope on L1 that indicates capsid uncoating. This uncoating defect was accompanied by a delay in the proteolysis of both L1 and L2 in mutated HPV-16 PsVs. Taken together, these studies indicate that phosphorylation of L2 during virus assembly plays an important role in optimal uncoating of virions during infection, suggesting that phosphorylation of the viral capsid proteins contributes to infectious entry. IMPORTANCE The papillomavirus L2 capsid protein plays an essential role in infectious entry, where it directs the successful trafficking of incoming viral genomes to the nucleus. However, nothing is known about how potential posttranslational modifications may affect different aspects of capsid assembly or infectious entry. In this study, we report the first phospho-specific modification of the BPV-1 and HPV-16 L2 capsid proteins. The phospho-acceptor site is very highly conserved across multiple papillomavirus types, indicating a highly conserved function within the L2 protein and the viral capsid. We show that this modification plays an essential role in infectious entry, where it modulates susceptibility of the incoming virus to capsid disassembly. These studies therefore define a completely new means of regulating the papillomavirus L2 proteins, a regulation that optimizes endocytic processing and subsequent completion of the infectious entry pathway.

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“…The virions are released through spontaneous epithelial cell shedding at the uppermost epithelial cell layers. Although the function of the HPV proteins E1^E4 and E5 remains enigmatic, E1^E4 is believed to play a role in the HPV late infection phase as it rearranges cellular cytoskeleton to enhance virion release [ 31 ], whereas E5 appears to aid in the evasion of the immune system via affecting the endocytic trafficking as well as to increase the cellular proliferation capacity [ 32 , 33 ].…”

Section: Hpv Life Cyclementioning

confidence: 99%

Role of Viral Ribonucleoproteins in Human Papillomavirus Type 16 Gene Expression

Kajitani

Schwartz

2020

Viruses

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Human papillomaviruses (HPVs) depend on the cellular RNA-processing machineries including alternative RNA splicing and polyadenylation to coordinate HPV gene expression. HPV RNA processing is controlled by cis-regulatory RNA elements and trans-regulatory factors since the HPV splice sites are suboptimal. The definition of HPV exons and introns may differ between individual HPV mRNA species and is complicated by the fact that many HPV protein-coding sequences overlap. The formation of HPV ribonucleoproteins consisting of HPV pre-mRNAs and multiple cellular RNA-binding proteins may result in the different outcomes of HPV gene expression, which contributes to the HPV life cycle progression and HPV-associated cancer development. In this review, we summarize the regulation of HPV16 gene expression at the level of RNA processing with focus on the interactions between HPV16 pre-mRNAs and cellular RNA-binding factors.

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Papillomaviruses and Endocytic Trafficking

Cited by 37 publications

References 205 publications

Human Papillomavirus 16 Capsids Mediate Nuclear Entry during Infection

Human Papillomavirus 16 Capsids Mediate Nuclear Entry during Infection

Phosphorylation of Human Papillomavirus Type 16 L2 Contributes to Efficient Virus Infectious Entry

Role of Viral Ribonucleoproteins in Human Papillomavirus Type 16 Gene Expression

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