The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses

Linda Gräßel; Laura Aline Fast; Konstanze D Scheffer; Fatima Boukhallouk; Gilles A Spoden; Stefan Tenzer; Klaus Boller; Ruzica Bago; Sundaresan Rajesh; Michael Overduin; Fedor Berditchevski; Luise Florin

doi:10.1038/srep32337

The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses

Linda Gräßel, Laura Aline Fast, Konstanze D Scheffer, Fatima Boukhallouk, Gilles A Spoden, Stefan Tenzer, Klaus Boller, Ruzica Bago, Sundaresan Rajesh, Michael Overduin, Fedor Berditchevski^*, Luise Florin^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

47 Citations (Scopus)

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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.

Original language	English
Article number	32337
Number of pages	18
Journal	Scientific Reports
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/srep32337
Publication status	Published - 31 Aug 2016

Keywords

Calcium-Binding Proteins/chemistry
Carcinogenesis/genetics
Cell Cycle Proteins/chemistry
Endocytosis/genetics
Endosomal Sorting Complexes Required for Transport/chemistry
Female
HeLa Cells
Human papillomavirus 16/genetics
Human papillomavirus 18/genetics
Human papillomavirus 31/genetics
Humans
Multiprotein Complexes/chemistry
Papillomavirus Infections/genetics
Protein Binding
Protein Transport/genetics
Syntenins/genetics
Tetraspanin 30/chemistry
Uterine Cervical Neoplasms/genetics

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10.1038/srep32337Licence: Creative Commons: Attribution (CC BY)

GräßelL2016CD63Final published version, 8.15 MBLicence: Creative Commons: Attribution (CC BY)

Molecular Basis for the Trafficking of Transmembrane Proteins Through Ubiquitin, Syntenin-1 and Tollip Complexes
Berditchevski, F. (Principal Investigator), Sundaresan, R. (Co-Investigator) & Overduin, M. (Co-Investigator)
Biotechnology & Biological Sciences Research Council
30/11/13 → 29/11/16
Project: Research Councils

Cite this

@article{6192fce534e94bb584e6e73d28029c79,

title = "The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses",

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.",

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author = "Linda Gr{\"a}{\ss}el and Fast, \{Laura Aline\} and Scheffer, \{Konstanze D\} and Fatima Boukhallouk and Spoden, \{Gilles A\} and Stefan Tenzer and Klaus Boller and Ruzica Bago and Sundaresan Rajesh and Michael Overduin and Fedor Berditchevski and Luise Florin",

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AU - Fast, Laura Aline

AU - Scheffer, Konstanze D

AU - Boukhallouk, Fatima

AU - Spoden, Gilles A

AU - Tenzer, Stefan

AU - Boller, Klaus

AU - Bago, Ruzica

AU - Rajesh, Sundaresan

AU - Overduin, Michael

AU - Berditchevski, Fedor

AU - Florin, Luise

PY - 2016/8/31

Y1 - 2016/8/31

N2 - 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.

AB - 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.

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KW - Carcinogenesis/genetics

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KW - Human papillomavirus 18/genetics

KW - Human papillomavirus 31/genetics

KW - Humans

KW - Multiprotein Complexes/chemistry

KW - Papillomavirus Infections/genetics

KW - Protein Binding

KW - Protein Transport/genetics

KW - Syntenins/genetics

KW - Tetraspanin 30/chemistry

KW - Uterine Cervical Neoplasms/genetics

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VL - 6

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 32337

ER -

The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses

Abstract

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Molecular Basis for the Trafficking of Transmembrane Proteins Through Ubiquitin, Syntenin-1 and Tollip Complexes

Cite this