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.
Highlights
Recent research has led to a more detailed picture of human papillomaviruses (HPV) entry
We have previously reported that HPV16 pseudoviruses (PsV) colocalise with tetraspanin CD63 on the plasma membrane and in endosomes of infected HeLa cells[22]
Previous data revealed that various oncogenic human papillomaviruses (HPV) enter cells via a novel endocytosis mechanism[22,24,26,40]
Summary
Recent research has led to a more detailed picture of HPV entry. The initial events of HPV infection including binding to target cells and transition towards the entry points have been characterized[2,4,5,6]. We investigated the role of tetraspanin CD63 and its cytoplasmic partner syntenin-1 in HPV infection Both CD63 and syntenin-1 are abundant in MVEs and known to regulate endocytic trafficking of associated cargos[41,42,43]. We established that this complex controls post-endocytosis trafficking of the virus to MVEs through a mechanism involving ALG-2-interacting protein X (ALIX), a recently described partner of syntenin-144 which regulates MVE biogenesis. Together, these results identify the CD63-syntenin-1-ALIX complex as a key component of a novel trafficking pathway which regulates post-endocytic sorting of HPV
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