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J Cell Physiol. 2018 May;233(5):4137-4155. doi: 10.1002/jcp.26219. Epub 2017 Dec 18.

Discovery and characterization of novel trans-spliced products of human polyoma JC virus late transcripts from PML patients.

Author information

1
Laboratory of Molecular Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.

Abstract

Although the human neurotropic polyomavirus, JC virus (JCV), was isolated almost a half century ago, understanding the molecular mechanisms governing its biology remains highly elusive. JCV infects oligodendrocytes and astrocytes in the central nervous system (CNS) and causes a rare fatal brain disease known as progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals including AIDS. It has a small circular DNA genome (∼5 kb) and generates two primary transcripts from its early and late coding regions, producing several predicted alternatively spliced products mainly by cis-splicing. Here, we report the discovery and characterization of two novel open reading frames (ORF1 and ORF2) associated with JCV late transcripts, generated by an unusual splicing process called trans-splicing. These ORFs result from (i) the trans-splicing of two different lengths of the 5'-short coding region of VP1 between the coding regions of agnoprotein and VP2 after replacing the intron located between these two coding regions and (ii) frame-shifts occurring within the VP2 coding sequences terminated by a stop codon. ORF1 and ORF2 are capable of encoding 58 and 72 aa long proteins respectively and are expressed in infected cells and PML patients. Each ORF protein shares a common coding region with VP1 and has a unique coding sequence of their own. When the expression of the unique coding regions of ORFs is blocked by a stop codon insertion in the viral background, the mutant virus replicates less efficiently when compared to wild-type, suggesting that the newly discovered ORFs play critical roles in the JCV life cycle.

KEYWORDS:

BK virus; DNA replication; JC virus; ORF; RNA splicing; SV40; VP1; VP2; cis- and trans-splicing; merkel cell carcinoma virus; polyomavirus; progressive multifocal leukoencephalopathy; transcription

PMID:
29044559
PMCID:
PMC5805571
[Available on 2019-05-01]
DOI:
10.1002/jcp.26219

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