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.
authors: Department of Medical Microbiology and Hygiene, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors: Linda
authors: L
authors: Gräßel
authors: Department of Medical Microbiology and Hygiene, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors: Laura Aline
authors: LA
authors: Fast
authors: Department of Medical Microbiology and Hygiene, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors: Konstanze D
authors: KD
authors: Scheffer
authors: Department of Medical Microbiology and Hygiene, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors: Fatima
authors: F
authors: Boukhallouk
authors: Department of Medical Microbiology and Hygiene, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors: Gilles A
authors: GA
authors: Spoden
authors: Department of Immunology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: Stefan
authors: S
authors: Tenzer
authors: Paul Ehrlich Institute, Langen, Germany.
authors: Klaus
authors: K
authors: Boller
authors: School of Cancer Sciences and Department of Pathology, The University of Birmingham, Birmingham, United Kingdom.
authors: Ruzica
authors: R
authors: Bago
authors: School of Cancer Sciences and Department of Pathology, The University of Birmingham, Birmingham, United Kingdom.
authors: Sundaresan
authors: S
authors: Rajesh
authors: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
authors: Michael
authors: M
authors: Overduin
authors: School of Cancer Sciences and Department of Pathology, The University of Birmingham, Birmingham, United Kingdom.
authors: Fedor
authors: F
authors: Berditchevski
authors: Department of Medical Microbiology and Hygiene, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors: Luise
authors: L
authors: Florin
mesh_terms: D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics*; D004705:Endocytosis / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity; D052161:Human papillomavirus 18 / Q000235:genetics / Q000472:pathogenicity; D058952:Human papillomavirus 31 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D053676:Syntenins / Q000235:genetics*; D060149:Tetraspanin 30 / Q000737:chemistry / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: C554586:CD63 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D046912:Multiprotein Complexes; C117020:PDCD6IP protein, human; C109621:SDCBP protein, human; D053676:Syntenins; D060149:Tetraspanin 30