Most non-enveloped viruses exit their host cells following cell lysis, which involves breakdown of the cell membrane and death of the host cell, and which is presumably the final result of an increase in plasma membrane permeability. JC virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML) and belongs to the polyomavirus family, which have non-enveloped virions. The extracellular release of mature progeny polyomavirus virions has been suggested to occur when cells disintegrate or rupture; however, the molecular mechanism(s) employed by JCV to induce cell lysis and facilitate virion release remain elusive. The late coding region of JCV encodes a small and basic regulatory protein, the agnoprotein, whose functions in the virus life cycle remain unclear. Viroporins are a group of proteins that modify the permeability of cellular membranes and promote the release of viral particles from infected cells. These proteins are not essential for the replication of viruses, but their presence often enhances virus growth. This paper demonstrates that the 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. These observations suggest that the process of virion release of this non-enveloped DNA virus is highly regulated by a single virus protein.
The Human Polyoma JC Virus Agnoprotein Acts as a Viroporin. 2010 PLoS Pathog 6(3): e1000801. doi: 10.1371/journal.ppat.1000801
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.
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