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

• Published in: Scientific reports 2016-08, Vol.6 (1), p.32337, Article 32337
• Main Authors: Gräßel, Linda, Fast, Laura Aline, Scheffer, Konstanze D., Boukhallouk, Fatima, Spoden, Gilles A., Tenzer, Stefan, Boller, Klaus, Bago, Ruzica, Rajesh, Sundaresan, Overduin, Michael, Berditchevski, Fedor, Florin, Luise
• Format: Article
• Language: English
• Subjects: 13/31; 13/89; 14; 14/28; 14/63; 631/326/596/2560; 631/80/2023; 82; 82/103; 82/58; 82/80; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - genetics; Carcinogenesis - genetics; CD63 antigen; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Clathrin; Electron microscopy; Endocytosis - genetics; Endosomal Sorting Complexes Required for Transport - chemistry; Endosomal Sorting Complexes Required for Transport - genetics; Endosomes; Female; HeLa Cells; Human papillomavirus; Human papillomavirus 16 - genetics; Human papillomavirus 16 - pathogenicity; Human papillomavirus 18 - genetics; Human papillomavirus 18 - pathogenicity; Human papillomavirus 31 - genetics; Human papillomavirus 31 - pathogenicity; Humanities and Social Sciences; Humans; Immunofluorescence; Infectivity; multidisciplinary; Multiprotein Complexes - chemistry; Multiprotein Complexes - genetics; Papillomaviridae; Papillomavirus Infections - genetics; Papillomavirus Infections - pathology; Papillomavirus Infections - virology; Protein Binding; Protein Transport - genetics; Proteins; Science; Syntenins - genetics; Tetraspanin 30 - chemistry; Tetraspanin 30 - genetics; Uncoating; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep32337

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.