The T antigen locus of Merkel cell polyomavirus downregulates human Toll-like receptor 9 expression.
Establishment of a chronic infection is a key event in virus-mediated carcinogenesis. Several cancer-associated, double-stranded DNA (dsDNA) viruses act via their oncoproteins to downregulate Toll-like receptor 9 (TLR9), a key receptor in the host innate immune response that senses viral or bacterial dsDNA. A novel oncogenic virus, Merkel cell polyomavirus (MCPyV), has been recently identified that causes up to 80% of Merkel cell carcinomas (MCCs). However, it is not yet known whether this oncogenic virus also disrupts immune-related pathways. We find that MCPyV large T antigen (LT) expression downregulates TLR9 expression in epithelial and MCC-derived cells. Accordingly, silencing of LT expression results in upregulation of mRNA TLR9 levels. In addition, small T antigen (sT) also appears to inhibit TLR9 expression, since inhibition of its expression also resulted in an increase of TLR9 mRNA levels. LT inhibits TLR9 expression by decreasing the mRNA levels of the C/EBPβ transactivator, a positive regulator of the TLR9 promoter. Chromatin immunoprecipitation reveals that C/EBPβ binding at a C/EBPβ response element (RE) in the TLR9 promoter is strongly inhibited by expression of MCPyV early genes and that mutation of the C/EBP RE prevents MCPyV downregulation of TLR9. A survey of BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), KI polyomavirus (KIPyV), MCPyV, simian virus 40 (SV40), and WU polyomavirus (WUPyV) early genes revealed that only BKPyV and MCPyV are potent inhibitors of TLR9 gene expression. MCPyV LT targeting of C/EBP transactivators is likely to play an important role in viral persistence and potentially inhibit host cell immune responses during MCPyV tumorigenesis.
International Agency for Research on Cancer, Lyon, France.
Naveed
N
Shahzad
Masahiro
M
Shuda
Tarik
T
Gheit
Hyun Jin
HJ
Kwun
Iris
I
Cornet
Djamel
D
Saidj
Claudia
C
Zannetti
Uzma
U
Hasan
Yuan
Y
Chang
Patrick S
PS
Moore
Rosita
R
Accardi
Massimo
M
Tommasino
D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D018862:Merkel Cells / Q000378:metabolism / Q000821:virology; D059965:Merkel cell polyomavirus / Q000235:genetics / Q000378:metabolism*; D027601:Polyomavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D011401:Promoter Regions, Genetic; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000378:metabolism; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology
D000957:Antigens, Viral, Tumor; D051217:Toll-Like Receptor 9