Entry of Human Papillomavirus Type 16 by Actin-Dependent, Clathrin- and Lipid Raft-Independent Endocytosis

Autor: Peter Blattmann, Patricia M. Day, Lena Kühling, Mario Schelhaas, Bhavin Shah, Ari Helenius, John T. Schiller, Michael Holzer
Rok vydání: 2012
Předmět:
viruses
Endocytic cycle
Molecular Cell Biology
lcsh:QH301-705.5
Protein Kinase C
Human papillomavirus 16
0303 health sciences
biology
Pinocytosis
030302 biochemistry & molecular biology
Endocytosis
3. Good health
Cell biology
Infectious Diseases
Vesicular stomatitis virus
Medicine
Membranes and Sorting
Cellular Types
Signal Transduction
Research Article
lcsh:Immunologic diseases. Allergy
Sodium-Hydrogen Exchangers
Endosome
Immunology
Semliki Forest virus
Caveolins
Microbiology
Clathrin
Virus
03 medical and health sciences
Membrane Microdomains
Virology
Genetics
Humans
Biology
Molecular Biology
030304 developmental biology
Papillomavirus Infections
Virus Internalization
biology.organism_classification
Molecular biology
Actins
lcsh:Biology (General)
p21-Activated Kinases
biology.protein
Parasitology
lcsh:RC581-607
HeLa Cells
Zdroj: PLoS Pathogens, 8 (4)
PLoS Pathogens
PLoS Pathogens, Vol 8, Iss 4, p e1002657 (2012)
ISSN: 1553-7374
DOI: 10.1371/journal.ppat.1002657
Popis: Infectious endocytosis of incoming human papillomavirus type 16 (HPV-16), the main etiological agent of cervical cancer, is poorly characterized in terms of cellular requirements and pathways. Conflicting reports attribute HPV-16 entry to clathrin-dependent and -independent mechanisms. To comprehensively describe the cell biological features of HPV-16 entry into human epithelial cells, we compared HPV-16 pseudovirion (PsV) infection in the context of cell perturbations (drug inhibition, siRNA silencing, overexpression of dominant mutants) to five other viruses (influenza A virus, Semliki Forest virus, simian virus 40, vesicular stomatitis virus, and vaccinia virus) with defined endocytic requirements. Our analysis included infection data, i.e. GFP expression after plasmid delivery by HPV-16 PsV, and endocytosis assays in combination with electron, immunofluorescence, and video microscopy. The results indicated that HPV-16 entry into HeLa and HaCaT cells was clathrin-, caveolin-, cholesterol- and dynamin-independent. The virus made use of a potentially novel ligand-induced endocytic pathway related to macropinocytosis. This pathway was distinct from classical macropinocytosis in regards to vesicle size, cholesterol-sensitivity, and GTPase requirements, but similar in respect to the need for tyrosine kinase signaling, actin dynamics, Na+/H+ exchangers, PAK-1 and PKC. After internalization the virus was transported to late endosomes and/or endolysosomes, and activated through exposure to low pH.
Author Summary Human papillomavirus type 16 is the main etiological agent of cervical cancer. Despite advances in our understanding of transformation and cancer progression, as well as preventative vaccination strategies, the early events in papillomavirus infections are incompletely understood. Here, we investigated which strategies and cellular mechanisms the virus uses to enter epithelial cells. Entry was slow and asynchronous likely due to several structural alterations, which needed to occur on the cell exterior. Interestingly, the virus hijacked a potentially novel pathway of endocytosis for entry, which was distinct from classical macropinocytosis in regards to vesicle size, cholesterol-sensitivity, and GTPase requirements, but similar in respect to tyrosine kinase signaling, actin dynamics, Na+/H+ exchangers, PAK-1 and PKC requirements. This cellular mechanism may also be used by other viruses such as influenza A virus, echo virus 1, and choriomeningitis virus.
Databáze: OpenAIRE
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