Leukemia virus long terminal repeat activates NFκB 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 trails 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 call also be activated by NF kappa B, and because the antiapoptotic and growth promoting activities of NF kappa B have been implicated in leukemogenesis, we investigated whether FeLV U3-LTR call activate NF kappa B signaling. Here, we demonstrate that FeLV U3-LTR indeed upregulates the NF kappa B signaling pathway via activation of Ras-Raf-I kappa B kinase (IKK) and degradation of I kappa B. UR-mediated transcriptional activation of genes did not require new protein synthesis suggesting all 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 NF kappa B by the LTR. Our Study thus demonstrates involvement of a TLR3-dependent but PKR-independent dsRNA-mediated signaling pathway for NF kappa B activation and thus provides a new mechanistic explanation of LTR-mediated cellular gene transactivation. (c) 2005 Elsevier Inc. All rights reserved.