Abstract
Virus infections can result in a range of cellular injuries and commonly this involves both the plasma and intracellular membranes, resulting in enhanced permeability. Viroporins are a group of proteins that interact with plasma membranes modifying permeability and can promote the release of viral particles. While these proteins are not essential for virus replication, their activity certainly promotes virus growth. Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease resulting from lytic infection of oligodendrocytes by the polyomavirus JC virus (JCV). The genome of JCV encodes six major proteins including a small auxiliary protein known as agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to viral propagation at various stages in the replication cycle, including transcription, translation, processing of late viral proteins, assembly of virions, and viral propagation. Previous studies from our and other laboratories have indicated that JCV agnoprotein plays an important, although as yet incompletely understood role in the propagation of JCV. Here, we demonstrate that agnoprotein possesses properties commonly associated with viroporins. Our findings demonstrate that: (i) A deletion mutant of agnoprotein is defective in virion release and viral propagation; (ii) Agnoprotein localizes to the ER early in infection, but is also found at the plasma membrane late in infection; (iii) Agnoprotein is an integral membrane protein and forms homo-oligomers; (iv) Agnoprotein enhances permeability of cells to the translation inhibitor hygromycin B; (v) Agnoprotein induces the influx of extracellular Ca2+; (vi) The basic residues at amino acid positions 8 and 9 of agnoprotein key are determinants of the viroporin activity. The viroporin-like properties of agnoprotein result in increased membrane permeability and alterations in intracellular Ca2+ homeostasis leading to membrane dysfunction and enhancement of virus release.
Highlights
Replication of viruses involves an extracellular step in the viral life cycle, involving the release of virus particles from infected cells and subsequent infection of target cells
Viroporins are a group of proteins that modify the permeability of cellular membranes and promote the release of viral particles from infected cells
We demonstrate that the JC virus (JCV) agnoprotein forms homo-oligomers as an integral membrane protein and acts as a viroporin, and that expression of agnoprotein results in plasma membrane permeabilization and virion release
Summary
Replication of viruses involves an extracellular step in the viral life cycle, involving the release of virus particles from infected cells and subsequent infection of target cells. It has been previously suggested that extracellular exit of the mature progeny virions of SV40 and JCV, which efficiently proliferate in the nuclei, occurs when cells disintegrate or rupture as part of their dying process. It remains unclear whether these virions employ specific molecular mechanism(s) which may contribute to or regulate cell lysis. More recent studies have suggested that individual viral proteins may contribute to the enhancement of plasma membrane permeability and release of progeny virions of a number of nonenveloped viruses, including poliovirus, rotavirus, and coxsackievirus [3] [4] [5] [6] [7]. Viroporins are integral membrane proteins which vary in size from about 60–120 amino acids, possessing at least one hydrophobic stretch able to form an amphipatic a-helix
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