Abstract
Circular RNAs (circRNAs) are a conserved class of RNAs with diverse functions, including serving as messenger RNAs that are translated into peptides. Here we describe circular RNAs generated by human polyomaviruses (HPyVs), some of which encode variants of the previously described alternative large T antigen open reading frame (ALTO) protein. Circular ALTO RNAs (circALTOs) can be detected in virus positive Merkel cell carcinoma (VP-MCC) cell lines and tumor samples. CircALTOs are stable, predominantly located in the cytoplasm, and N6-methyladenosine (m6A) modified. The translation of MCPyV circALTOs into ALTO protein is negatively regulated by MCPyV-generated miRNAs in cultured cells. MCPyV ALTO expression increases transcription from some recombinant promoters in vitro and upregulates the expression of multiple genes previously implicated in MCPyV pathogenesis. MCPyV circALTOs are enriched in exosomes derived from VP-MCC lines and circALTO-transfected 293T cells, and purified exosomes can mediate ALTO expression and transcriptional activation in MCPyV-negative cells. The related trichodysplasia spinulosa polyomavirus (TSPyV) also expresses a circALTO that can be detected in infected tissues and produces ALTO protein in cultured cells. Thus, human polyomavirus circRNAs are expressed in human tumors and infected tissues and express proteins that have the potential to modulate the infectious and tumorigenic properties of these viruses.
Highlights
About a dozen polyomaviruses infect humans [1]
Human polyomaviruses (HPyV) have been linked to diseases including Merkel cell carcinoma (MCC), a skin cancer caused by Merkel cell polyomavirus (MCPyV), and skin and hair eruptions caused by trichodysplasia spinulosa polyomavirus (TSPyV)
We discover that HPyVs generate single-stranded, circular RNAs in affected tissues
Summary
About a dozen polyomaviruses infect humans [1]. Merkel cell carcinoma (MCC) is a rare, deadly skin cancer linked to Merkel cell polyomavirus (MCV or MCPyV) infection in 80% of cases [2]. The polyomavirus early region (ER) encodes for small T-antigen (sT) and large T-antigen (LT), while the late region contains late structural proteins VP1 and VP2 [8,9,10]. In a subset of Alphapolyomaviruses, including MCPyV and TSPyV, the early region has been shown to generate several variably spliced transcripts, including a transcript that encodes a protein in an alternate reading frame from large T antigen (ALTO) [13,14]. MPyV MT has transforming activity and has been a useful tool to study cellular transformation [16], the precise function of human ALTO proteins remain unclear
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