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Viroporin activity of the JC polyomavirus is regulated by interactions with the adaptor protein complex 3

Significance Viroporins are small, hydrophobic viral proteins that form pores on host cell membranes, and their expression can increase the production of progeny virus particles. Recently, we have shown that human JC polyomavirus agnoprotein acts as a viroporin. We have investigated the role of host cellular proteins in the viroporin activity of the agnoprotein. We demonstrated that an interaction of the agnoprotein with the δ subunit of AP-3 prevents AP-3–mediated vesicular trafficking and blocks the targeted transport of the agnoprotein for lysosomal degradation. These findings demonstrate a previously undescribed paradigm in virus–host interactions regulating virus replication and suggest that viroporins of other viruses may also be regulated by specific interactions with host cellular proteins. Viroporins, which are encoded by a wide range of animal viruses, oligomerize in host cell membranes and form hydrophilic pores that can disrupt a number of physiological properties of the cell. Little is known about the relationship between host cell proteins and viroporin activity. The human JC polyomavirus (JCV) is the causative agent of progressive multifocal leukoencephalopathy. The JCV-encoded agnoprotein, which is essential for viral replication, has been shown to act as a viroporin. Here we demonstrate that the JCV agnoprotein specifically interacts with adaptor protein complex 3 through its δ subunit. This interaction interrupts adaptor protein complex 3–mediated vesicular trafficking with suppression of the targeting of the protein to the lysosomal degradation pathway and instead permits the transport of agnoprotein to the cell surface with resulting membrane permeabilization. The findings demonstrate a previously undescribed paradigm in virus–host interactions allowing the host to regulate viroporin activity and suggest that the viroporins of other viruses may also be highly regulated by specific interactions with host cell proteins.