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Abstract
Trafficking of human papillomaviruses to the Golgi apparatus during virus entry requires retromer, an endosomal coat protein complex that mediates the vesicular transport of cellular transmembrane proteins from the endosome to the Golgi apparatus or the plasma membrane. Here we show that the HPV16 L2 minor capsid protein is a retromer cargo, even though L2 is not a transmembrane protein. We show that direct binding of retromer to a conserved sequence in the carboxy-terminus of L2 is required for exit of L2 from the early endosome and delivery to the trans-Golgi network during virus entry. This binding site is different from known retromer binding motifs and can be replaced by a sorting signal from a cellular retromer cargo. Thus, HPV16 is an unconventional particulate retromer cargo, and retromer binding initiates retrograde transport of viral components from the endosome to the trans-Golgi network during virus entry. We propose that the carboxy-terminal segment of L2 protein protrudes through the endosomal membrane and is accessed by retromer in the cytoplasm.
Highlights
The human papillomaviruses are small non-enveloped viruses responsible for approximately 5% of human cancer deaths worldwide [1]
Because retromer is required for the delivery of HPV16 to the Golgi apparatus and initiates endosome-to-Golgi transport of various cellular proteins, we hypothesized that a viral protein might bind to retromer
HeLa cells were infected with wild-type and mutant PsV stocks containing the same number of encapsidated reporter plasmids, corresponding to a multiplicity of infection (MOI) of approximately 0.5 for wildtype, and successful infection was measured two days later by flow cytometry for GFP fluorescence
Summary
The human papillomaviruses are small non-enveloped viruses responsible for approximately 5% of human cancer deaths worldwide [1]. Initial binding of virus to cells is mediated by the interaction between the L1 capsid protein and heparan sulfate proteoglycans [5,6,7,8]. Cell cycle progression and nuclear envelope breakdown appear required for HPV entry into the nucleus, where viral gene expression and DNA replication occur [25,26]. The L1 protein dissociates from the viral DNA, but the 473-amino acid L2 protein is required for efficient trafficking of the viral genome to the nucleus and remains associated with the genome during nuclear entry [20,27,28,29,30,31,32,33,34]
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