Human papillomavirus type 16 does not require cathepsin L or B for infection

Calton, Christine M.; Schlegel, Angela M.; Chapman, Janice A.; Campos, Samuel K.

doi:10.1099/vir.0.053694-0

Cited by 12 publications

(20 citation statements)

References 16 publications

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“…In conclusion, cathepsin-mediated cleavage of L1 was not required for infection, supporting previous results (23,32).…”

Section: Hpv16 L1 Is Proteolytically Cleaved During Infectionsupporting

confidence: 78%

“…The cathepsin-mediated cleavage of L1 in the absence of autophagy is likely the result of postuncoating degradation of the major capsid protein, as previously suggested (32). Uncoating occurs when cathepsin activity is inhibited.…”

Section: Hpv16 L1 Is Proteolytically Cleaved During Infectionmentioning

confidence: 65%

“…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.…”

mentioning

confidence: 95%

“…Previous reports indicate proteolytic processing of HPV16 L1 during cell entry (30)(31)(32). To analyze the potential contribution of cellular proteases to proteolytic processing and uncoating of HPV16, we first followed the cleavage pattern of L1 during entry into HeLa and HaCaT cells.…”

Section: Hpv16 L1 Is Proteolytically Cleaved During Infectionmentioning

confidence: 99%

See 4 more Smart Citations

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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“…In conclusion, cathepsin-mediated cleavage of L1 was not required for infection, supporting previous results (23,32).…”

Section: Hpv16 L1 Is Proteolytically Cleaved During Infectionsupporting

confidence: 78%

Section: Hpv16 L1 Is Proteolytically Cleaved During Infectionmentioning

confidence: 65%