The role of NH4Cl and cysteine proteases in Human Papillomavirus type 16 infection

Dabydeen, Sarah A.; Meneses, Patricio

doi:10.1186/1743-422x-6-109

Cited by 31 publications

(34 citation statements)

References 41 publications

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“…In line with previous studies (23,30,32,33), most of the proteolytic processing occurred in endolysosomes by cysteine cathepsins. Dispensable for infection, the cathepsin-mediated cleavages were likely the result of postuncoating L1 degradation and, in part, of an autophagic response to infection.…”

Section: Discussionsupporting

confidence: 77%

“…The role of cysteine cathepsins in HPV entry has been previously analyzed with different results (23,32,33). Although two studies suggested a cathepsin-mediated cleavage of L1, Dabydeen and Meneses (33) claimed a productive role for it in virus uncoating, whereas Calton and colleagues (32) suggested a role for postuncoating degradation.…”

Section: Hpv16 L1 Is Proteolytically Cleaved During Infectionmentioning

confidence: 99%

“…In addition, it remains unclear how the covalent interpentameric disulfide bonds are broken, which would be a prerequisite to removing the pentameric capsomers from the subviral particles by cyclophilins. In addition to reduction or isomerization of the disulfides, a further mechanism to unlink pentamers may be proteolytic processing of L1 in the endosomal pathway, which has been previously observed (30)(31)(32)(33). However, the role of L1 proteolysis for HPV infection is still under debate since different studies reached divergent conclusions on the necessity of L1 proteolysis for infection.…”

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confidence: 95%

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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: Discussionsupporting

confidence: 77%

Section: Hpv16 L1 Is Proteolytically Cleaved During Infectionmentioning

confidence: 99%

mentioning

confidence: 95%

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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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“…While the potential receptors and the mode of endocytosis are still highly questionable, a majority of studies agree that exposure to low pH in late endosomes or lysosomes is critical for viral uncoating and, consequently, for efficient PV infection (3,5,8,19). In the case of the HPV-16 L2 interaction with SNX17, this seems to aid lysosomal escape (12).…”

mentioning

confidence: 99%

“…We concluded that the infectivity of MCV is in general not affected by SNX17 silencing, suggesting that the observed reduction in PV infectivity following SNX17 silencing is directly related to the interaction between L2 and SNX17. While the potential receptors and the mode of endocytosis are still highly questionable, a majority of studies agree that exposure to low pH in late endosomes or lysosomes is critical for viral uncoating and, consequently, for efficient PV infection (3,5,8,19). In the case of the HPV-16 L2 interaction with SNX17, this seems to aid lysosomal escape (12).…”

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confidence: 99%

SNX17 Facilitates Infection with Diverse Papillomavirus Types

Bergant

Banks

2013

J Virol

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Previous studies have shown that the human papillomavirus type 16 (HPV-16) L2 capsid protein plays an essential role in viral infection, in part through its interaction with sorting nexin 17 (SNX17). We now show that this interaction between L2 and SNX17 is conserved across multiple PV types. Furthermore, we demonstrate that SNX17 is essential for infection with all PV types analyzed, indicating an evolutionarily highly conserved virus entry mechanism. Many of the more than 120 known human papillomaviruses (HPVs) cause sexually transmitted infections, with a subset of them being associated with the development of epithelial tumors and cancer (1). Infectious entry of HPVs is still poorly characterized in terms of the cellular proteins and endocytic pathways employed. It seems that some HPV types may have evolved different entry strategies (2, 3) or take advantage of cross talk between different routes of endocytosis (4,5). A recent study suggested that HPVs can usurp soluble cellular factors for interaction with a plethora of entry receptors, resulting in different routes of internalization (6). The HPV capsid, comprising the major L1 and minor L2 proteins, fulfills various roles in the establishment of a successful viral infection. L2 is critically involved in many steps of the infection process, although its precise functions in entry, intracellular trafficking, endosomal escape, and nuclear import of the viral genome have not been fully elucidated (7). While L2 is not essential for viral uncoating, it is critical for the escape of viral DNA from the endosomal compartment (8) and ultimately for aiding transport of the viral genome to the nucleus (9-11).We reported previously that the HPV-16 L2 interaction with a member of the sorting nexin family, SNX17, is essential for HPV-16 infection (12). SNX17 is localized in early endosomes and recycling tubules and is primarily involved in endosomal recycling (13,14). We showed that at least one putative SNX17 binding motif, NPxF/Y (PTB consensus binding motif) is present in L2s from diverse papillomavirus (PV) genera, indicating that this motif is evolutionarily highly conserved. A previous protein mass spectrometry analysis of HPV-11 L2 and HPV-16 L2 immunoprecipitates in HEK293 cells revealed that SNX17 is an interacting partner of both L2 proteins (12). To investigate whether SNX17 interacts with L2 proteins from diverse HPV genera, a series of pulldown assays with a panel of glutathione S-transferase (GST)-L2 proteins and endogenously derived SNX17 were performed. The results (Fig. 1A) confirmed the interaction between HPV-16 and HPV-11 L2 (genus Alpha) proteins and SNX17. The analysis was then extended to HPV-5 L2 (genus Beta), bovine papillomavirus type 1 (BPV-1) L2 (genus Delta), and cottontail rabbit papillomavirus type 1 (SfPV-1) L2 (genus Kappa). The results in Fig. 1A show interactions between these diverse L2 proteins and SNX17, although the interaction between SNX17 and SfPV L2 was consistently weaker.Previous analyses indicated that HPV-16 L2 bound SNX17 ...

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Principles of polyoma- and papillomavirus uncoating

Cerqueira

Schelhaas

2012

Med Microbiol Immunol

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Virus particles are vehicles for transmission of the viral genetic information between infected and uninfected cells and organisms. They have evolved to self-assemble, to serve as a protective shell for the viral genome during transfer, and to disassemble when entering a target cell. Disassembly during entry is a complex, multi-step process typically termed uncoating. Uncoating is triggered by multiple host-cell interactions. During cell entry, these interactions occur sequentially in different cellular compartments that the viruses pass through on their way to the site of replication. Here, we highlight the general principles of uncoating for two structurally related virus families, the polyoma- and papillomaviruses. Recent research indicates the use of different compartments and cellular interactions for uncoating despite their structural similarity.

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The role of NH4Cl and cysteine proteases in Human Papillomavirus type 16 infection

Cited by 31 publications

References 41 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

SNX17 Facilitates Infection with Diverse Papillomavirus Types

Principles of polyoma- and papillomavirus uncoating

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