Leukemia virus long terminal repeat activates NFkappaB pathway by a TLR3-dependent mechanism.
The long terminal repeat (LTR) region of leukemia viruses plays a critical role in tissue tropism and pathogenic potential of the viruses. We have previously reported that U3-LTR from Moloney murine and feline leukemia viruses (Mo-MuLV and FeLV) upregulates specific cellular genes in trans in an integration-independent way. The U3-LTR region necessary for this action does not encode a protein but instead makes a specific RNA transcript. Because several cellular genes transactivated by the U3-LTR can also be activated by NFkappaB, and because the antiapoptotic and growth promoting activities of NFkappaB have been implicated in leukemogenesis, we investigated whether FeLV U3-LTR can activate NFkappaB signaling. Here, we demonstrate that FeLV U3-LTR indeed upregulates the NFkappaB signaling pathway via activation of Ras-Raf-IkappaB kinase (IKK) and degradation of IkappaB. LTR-mediated transcriptional activation of genes did not require new protein synthesis suggesting an active role of the LTR transcript in the process. Using Toll-like receptor (TLR) deficient HEK293 cells and PKR(-/-) mouse embryo fibroblasts, we further demonstrate that although dsRNA-activated protein kinase R (PKR) is not necessary, TLR3 is required for the activation of NFkappaB by the LTR. Our study thus demonstrates involvement of a TLR3-dependent but PKR-independent dsRNA-mediated signaling pathway for NFkappaB activation and thus provides a new mechanistic explanation of LTR-mediated cellular gene transactivation.
Abujamra
Ana L
AL
Cancer Research Center, Boston University School of Medicine, 715 Albany Street, R908, Boston, MA 02118, USA.
Spanjaard
Remco A
RA
Akinsheye
Idowu
I
Zhao
Xiansi
X
Faller
Douglas V
DV
Ghosh
Sajal K
SK
D016475:3T3 Cells; D000818:Animals; D002415:Cats; D002460:Cell Line; D006801:Humans; D005256:Leukemia Virus, Feline / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008979:Moloney murine leukemia virus / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020079:Terminal Repeat Sequences / Q000235:genetics*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D016328:NF-kappa B; D051196:Toll-Like Receptor 3