Abstract
Human papillomaviruses enter host cells via a clathrin-independent endocytic pathway involving tetraspanin proteins. However, post-endocytic trafficking required for virus capsid disassembly remains unclear. Here we demonstrate that the early trafficking pathway of internalised HPV particles involves tetraspanin CD63, syntenin-1 and ESCRT-associated adaptor protein ALIX. Following internalisation, viral particles are found in CD63-positive endosomes recruiting syntenin-1, a CD63-interacting adaptor protein. Electron microscopy and immunofluorescence experiments indicate that the CD63-syntenin-1 complex controls delivery of internalised viral particles to multivesicular endosomes. Accordingly, infectivity of high-risk HPV types 16, 18 and 31 as well as disassembly and post-uncoating processing of viral particles was markedly suppressed in CD63 or syntenin-1 depleted cells. Our analyses also present the syntenin-1 interacting protein ALIX as critical for HPV infection and CD63-syntenin-1-ALIX complex formation as a prerequisite for intracellular transport enabling viral capsid disassembly. Thus, our results identify the CD63-syntenin-1-ALIX complex as a key regulatory component in post-endocytic HPV trafficking.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium-Binding Proteins / chemistry
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Calcium-Binding Proteins / genetics*
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Carcinogenesis / genetics
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / genetics*
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Endocytosis / genetics
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Endosomal Sorting Complexes Required for Transport / chemistry
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Endosomal Sorting Complexes Required for Transport / genetics*
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Female
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HeLa Cells
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Human papillomavirus 16 / genetics
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Human papillomavirus 16 / pathogenicity
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Human papillomavirus 18 / genetics
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Human papillomavirus 18 / pathogenicity
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Human papillomavirus 31 / genetics
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Human papillomavirus 31 / pathogenicity
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Humans
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / genetics
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Papillomavirus Infections / genetics*
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Papillomavirus Infections / pathology
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Papillomavirus Infections / virology
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Protein Binding
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Protein Transport / genetics
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Syntenins / genetics*
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Tetraspanin 30 / chemistry
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Tetraspanin 30 / genetics*
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Uterine Cervical Neoplasms / genetics*
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Uterine Cervical Neoplasms / pathology
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Uterine Cervical Neoplasms / virology
Substances
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CD63 protein, human
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Calcium-Binding Proteins
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Cell Cycle Proteins
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Endosomal Sorting Complexes Required for Transport
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Multiprotein Complexes
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PDCD6IP protein, human
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SDCBP protein, human
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Syntenins
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Tetraspanin 30