Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus

Rong Yang; Eunice E. Lee; Jiwoong Kim; Joon H. Choi; Elysha Kolitz; Yating Chen; Clair Crewe; Nicholas J.H. Salisbury; Philipp E. Schereri; Clay Cockerell; Taylor R. Smith; Leslie Rosen; Louisa Verlinden; Denise A. Galloway; Christopher B. Buck; Mariet C. Feltkamp; Christopher S. Sullivan; Richard C. Wang

doi:10.1371/journal.ppat.1009582

Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus

Rong Yang, Eunice E. Lee, Jiwoong Kim, Joon H. Choi, Elysha Kolitz, Yating Chen, Clair Crewe, Nicholas J.H. Salisbury, Philipp E. Schereri, Clay Cockerell, Taylor R. Smith, Leslie Rosen, Louisa Verlinden, Denise A. Galloway, Christopher B. Buck, Mariet C. Feltkamp, Christopher S. Sullivan, Richard C. Wang

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English (US)
Article number	e1009582
Journal	PLoS pathogens
Volume	17
Issue number	5
DOIs	https://doi.org/10.1371/journal.ppat.1009582
State	Published - May 2021

ASJC Scopus subject areas

Parasitology
Microbiology
Immunology
Molecular Biology
Genetics
Virology

Access to Document

10.1371/journal.ppat.1009582

Cite this

Yang, R., Lee, E. E., Kim, J., Choi, J. H., Kolitz, E., Chen, Y., Crewe, C., Salisbury, N. J. H., Schereri, P. E., Cockerell, C., Smith, T. R., Rosen, L., Verlinden, L., Galloway, D. A., Buck, C. B., Feltkamp, M. C., Sullivan, C. S., & Wang, R. C. (2021). Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus. PLoS pathogens, 17(5), Article e1009582. https://doi.org/10.1371/journal.ppat.1009582

Yang, R, Lee, EE, Kim, J, Choi, JH, Kolitz, E, Chen, Y, Crewe, C, Salisbury, NJH, Schereri, PE, Cockerell, C, Smith, TR, Rosen, L, Verlinden, L, Galloway, DA, Buck, CB, Feltkamp, MC, Sullivan, CS & Wang, RC 2021, 'Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus', PLoS pathogens, vol. 17, no. 5, e1009582. https://doi.org/10.1371/journal.ppat.1009582

@article{10d08fbd267e4f6e96638d43fd0fa369,

title = "Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus",

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.",

author = "Rong Yang and Lee, {Eunice E.} and Jiwoong Kim and Choi, {Joon H.} and Elysha Kolitz and Yating Chen and Clair Crewe and Salisbury, {Nicholas J.H.} and Schereri, {Philipp E.} and Clay Cockerell and Smith, {Taylor R.} and Leslie Rosen and Louisa Verlinden and Galloway, {Denise A.} and Buck, {Christopher B.} and Feltkamp, {Mariet C.} and Sullivan, {Christopher S.} and Wang, {Richard C.}",

note = "Publisher Copyright: Copyright: {\textcopyright} 2021 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2021",

month = may,

doi = "10.1371/journal.ppat.1009582",

language = "English (US)",

volume = "17",

journal = "PLoS pathogens",

issn = "1553-7366",

publisher = "Public Library of Science",

number = "5",

}

TY - JOUR

T1 - Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus

AU - Yang, Rong

AU - Lee, Eunice E.

AU - Kim, Jiwoong

AU - Choi, Joon H.

AU - Kolitz, Elysha

AU - Chen, Yating

AU - Crewe, Clair

AU - Salisbury, Nicholas J.H.

AU - Schereri, Philipp E.

AU - Cockerell, Clay

AU - Smith, Taylor R.

AU - Rosen, Leslie

AU - Verlinden, Louisa

AU - Galloway, Denise A.

AU - Buck, Christopher B.

AU - Feltkamp, Mariet C.

AU - Sullivan, Christopher S.

AU - Wang, Richard C.

N1 - Publisher Copyright: Copyright: © 2021 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85106373908&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85106373908&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1009582

DO - 10.1371/journal.ppat.1009582

M3 - Article

C2 - 33999949

AN - SCOPUS:85106373908

SN - 1553-7366

VL - 17

JO - PLoS pathogens

JF - PLoS pathogens

IS - 5

M1 - e1009582

ER -

Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this