Merkel cell polyomavirus small T antigen is a viral transcription activator that is essential for viral genome maintenance.
Humans
Merkel cell polyomavirus
/ metabolism
Antigens, Viral, Tumor
/ genetics
Viral Transcription
DNA Replication
Virus Replication
DNA, Viral
/ genetics
Carcinoma, Merkel Cell
Transcription Factors
/ metabolism
Skin Neoplasms
/ pathology
Genome, Viral
RNA, Messenger
/ metabolism
Polyomavirus Infections
/ metabolism
Tumor Virus Infections
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
08
08
2022
accepted:
01
12
2022
revised:
09
01
2023
pubmed:
28
12
2022
medline:
12
1
2023
entrez:
27
12
2022
Statut:
epublish
Résumé
Merkel cell polyomavirus (MCV) is a small DNA tumor virus that persists in human skin and causes Merkel cell carcinoma (MCC) in immunocompromised individuals. The multi-functional protein MCV small T (sT) activates viral DNA replication by stabilizing large T (LT) and promotes cell transformation through the LT stabilization domain (LTSD). Using MCVΔsT, a mutant MCV clone that ablates sT, we investigated the role of sT in MCV genome maintenance. sT was dispensable for initiation of viral DNA replication, but essential for maintenance of the MCV genome and activation of viral early and late gene expression for progression of the viral lifecycle. Furthermore, in phenotype rescue studies, exogenous sT activated viral DNA replication and mRNA expression in MCVΔsT through the LTSD. While exogenous LT expression, which mimics LT stabilization, increased viral DNA replication, it did not activate viral mRNA expression. After cataloging transcriptional regulator proteins by proximity-based MCV sT-host protein interaction analysis, we validated LTSD-dependent sT interaction with four transcriptional regulators: Cux1, c-Jun, BRD9, and CBP. Functional studies revealed Cux1 and c-Jun as negative regulators, and CBP and BRD9 as positive regulators of MCV transcription. CBP inhibitor A-485 suppressed sT-induced viral gene activation in replicating MCVΔsT and inhibited early gene expression in MCV-integrated MCC cells. These results suggest that sT promotes viral lifecycle progression by activating mRNA expression and capsid protein production through interaction with the transcriptional regulators. This activity is essential for MCV genome maintenance, suggesting a critical role of sT in MCV persistence and MCC carcinogenesis.
Identifiants
pubmed: 36574443
doi: 10.1371/journal.ppat.1011039
pii: PPATHOGENS-D-22-01383
pmc: PMC9829177
doi:
Substances chimiques
Antigens, Viral, Tumor
0
DNA, Viral
0
Transcription Factors
0
RNA, Messenger
0
BRD9 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1011039Subventions
Organisme : NCI NIH HHS
ID : P50 CA121973
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Informations de copyright
Copyright: © 2022 Rapchak 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.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Virol. 2003 Jan;77(1):665-72
pubmed: 12477869
Proc Natl Acad Sci U S A. 2015 May 12;112(19):5875-82
pubmed: 25883264
Mol Cell. 2010 Jun 11;38(5):700-11
pubmed: 20542002
J Virol. 1994 May;68(5):3138-44
pubmed: 8151779
Nat Rev Cancer. 2014 Oct;14(10):673-82
pubmed: 25190083
Front Genet. 2020 May 12;11:450
pubmed: 32477404
J Virol. 1999 May;73(5):4220-9
pubmed: 10196318
Cell. 2018 Jun 28;174(1):231-244.e12
pubmed: 29804834
Virology. 2009 Jan 20;383(2):183-7
pubmed: 19046593
RNA. 2003 May;9(5):607-17
pubmed: 12702819
J Virol. 2000 Jul;74(14):6348-57
pubmed: 10864645
J Virol. 2015 Nov 25;90(3):1544-56
pubmed: 26608318
Mol Biol Cell. 2002 Nov;13(11):3761-74
pubmed: 12429822
J Vis Exp. 2019 Feb 7;(144):
pubmed: 30799855
J Virol. 2010 Jul;84(14):7064-72
pubmed: 20444890
Cell. 2001 Aug 10;106(3):297-307
pubmed: 11509179
PLoS Pathog. 2017 Oct 13;13(10):e1006668
pubmed: 29028833
Virology. 2008 Jan 20;370(2):255-63
pubmed: 17936323
Viruses. 2022 Feb 25;14(3):
pubmed: 35336880
Cell. 1989 Jan 13;56(1):67-75
pubmed: 2521301
Cell Host Microbe. 2013 Aug 14;14(2):125-35
pubmed: 23954152
Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16272-7
pubmed: 18812503
Methods Mol Biol. 2009;564:359-72
pubmed: 19544034
PLoS One. 2011;6(7):e22468
pubmed: 21799863
Science. 2008 Feb 22;319(5866):1096-100
pubmed: 18202256
Nature. 1987 Jan 22-28;325(6102):368-72
pubmed: 3027570
Virus Genes. 2007 Dec;35(3):473-81
pubmed: 17957475
Virology. 2008 Sep 1;378(2):214-25
pubmed: 18614194
J Infect Dis. 2021 Oct 13;224(7):1160-1169
pubmed: 32060513
PLoS One. 2010 May 12;5(5):e10606
pubmed: 20485545
J Virol. 1990 Dec;64(12):5823-32
pubmed: 2173769
J Clin Invest. 2011 Sep;121(9):3623-34
pubmed: 21841310
Cell Host Microbe. 2016 Jun 8;19(6):775-87
pubmed: 27212661
Oncogene. 2001 Apr 30;20(19):2365-77
pubmed: 11402333
PLoS Pathog. 2022 Apr 1;18(4):e1010401
pubmed: 35363834
Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):20104-20114
pubmed: 31527246
Cell Rep. 2016 Nov 8;17(7):1858-1871
pubmed: 27829156
J Virol. 2009 Dec;83(23):12118-28
pubmed: 19759150
Cell. 1979 Feb;16(2):373-88
pubmed: 222459
Elife. 2021 Mar 11;10:
pubmed: 33704060
J Virol. 2015 Jan;89(1):35-47
pubmed: 25320307
PLoS Pathog. 2013;9(8):e1003558
pubmed: 23990782
J Virol. 2015 Apr;89(8):4191-200
pubmed: 25631078
Nature. 2017 Oct 5;550(7674):128-132
pubmed: 28953875
J Virol. 1986 Nov;60(2):768-70
pubmed: 3022009
Cancer Res. 2002 Nov 15;62(22):6625-33
pubmed: 12438259
PLoS Pathog. 2015 Sep 25;11(9):e1005166
pubmed: 26407100
J Virol. 1992 Mar;66(3):1804-8
pubmed: 1310784
Cell Host Microbe. 2010 Jun 25;7(6):509-15
pubmed: 20542254
Front Microbiol. 2018 Apr 11;9:713
pubmed: 29696010
PLoS Pathog. 2016 Nov 23;12(11):e1006020
pubmed: 27880818
Genes Genomics. 2020 Jun;42(6):691-698
pubmed: 32399935
Sci Rep. 2019 Sep 20;9(1):13653
pubmed: 31541118
PLoS Pathog. 2019 Jan 28;15(1):e1007543
pubmed: 30689667
PLoS Pathog. 2015 Jul 28;11(7):e1004974
pubmed: 26218535
J Virol. 1997 Jan;71(1):129-37
pubmed: 8985331
Proc Natl Acad Sci U S A. 2017 May 16;114(20):E4040-E4047
pubmed: 28461484