The agnoprotein of polyomavirus JC is released by infected cells: Evidence for Its cellular uptake by uninfected neighboring cells

Abstract

Poliomavirus JC replicates in glial cells in the brain, and causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). PML is usually seen in patients with underlying immunocompromised conditions, notably among AIDS patients and those on chronic immunosuppressive regimens. The late leader sequence of JC virus contains an open reading frame encoding a small regulatory protein called agnoprotein. Agnoprotein contributes to progressive viral infection by playing significant roles in viral replication cycle. Here, we demonstrate that agnoprotein can be detected in cell-free fractions of glial cultures infected with JCV, transfected with expression plasmids or transduced with adenovirus expression system. We also provide evidence that extracellular agnoprotein can be taken up by uninfected neighboring cells. These studies have revealed a novel phenomenon of agnoprotein during the viral life cycle with a potential of developing diagnostic and therapeutic interventions.

Oligomerization of neutral peptides derived from the JC virus agnoprotein through a cysteine residue

“…Similar change in CD spectra is reported for fibril forming peptides such as insulin (Zako et al 2009) and Aβ peptide (Tomaselli et al 2006). Recently, Agno was reported to exist outside of the infected cell (Otlu et al 2014). It is interesting to assume that the released Agno may form oligomers or aggregates with other β-sheet forming proteins such as myelin sheath (Kursula 2008) or amyloid beta fibrils (Giovanna et al 2010), resulting in various brain diseases.…”

Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy

“…Recently, it was found that the JCV late regulatory protein, agnoprotein, is able to be released from JCV‐infected cells . Because agnoprotein is only expressed by cells that are actively replicating the virus and is released into the extracellular matrix, it is possible that detection of agnoprotein in clinical samples could serve as a biomarker for JCV reactivation.…”

Emerging From the Unknown: Structural and Functional Features of Agnoprotein of Polyomaviruses

“…The precise mechanism of this phenomenon is currently unknown. However, recent findings by Otlu et al (2014) demonstrate that agnoprotein is readily released from the infected cells. Further analysis of these three Phe mutants in release assays by our laboratory demonstrate that each may play a significant role in this process, because high proportion of each Phe-mutant agnoprotein appears to be trapped in cells during the release process.…”

“…Two recent publications also argue against the membrane integration activity agnoprotein. In one of the reports, it was demonstrated that agnoprotein is released from infected and transfected cells into the culture medium (Otlu et al, ) suggesting that if agnoprotein is an integral component of the cell membrane, it is highly unlikely that it will be readily secreted into the cell culture medium unless one of the various forms of agnoprotein (monomeric, dimeric or oligomeric (Saribas et al, ) are favorably suitable for this process. In a second report, Johannessen et al () demonstrated that BKV agnoprotein interacts with α‐soluble N‐ethylmaleimide‐sensitive fusion attachment protein (α‐SNAP) (Johannessen et al, ), which is a ubiquitous and indispensable component of the membrane fusion machinery and is a part of a special membrane system such as Golgi apparatus, suggesting that agnoprotein may interact with cell surface molecules rather than inserting itself into the cell membranes.…”