title: Viroporin activity of the JC polyomavirus is regulated by interactions with the adaptor protein complex 3.
abstract: 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.
authors.affiliation: Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan.
authors.forename: Tadaki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Orba
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Makino
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sunden
authors.forename: Hideki
authors.initials: H
authors.lastname: Hasegawa
authors.forename: William W
authors.initials: WW
authors.lastname: Hall
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawa
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D007577:JC Virus / Q000235:genetics* / Q000378:metabolism*; D059748:Proteolysis; D022161:Transport Vesicles / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D033963:Adaptor Protein Complex 3; D054334:Viral Regulatory and Accessory Proteins; C042559:agnoprotein, polyomavirus; D000086082:Viroporin Proteins
keywords: intracellular vesicular trafficking; pathogen–host cell interaction