Alternative NF-κB Signaling Discriminates Induction of the Tumor Marker Fascin by the Viral Oncoproteins Tax-1 and Tax-2 of Human T-Cell Leukemia Viruses

Abstract

Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on classical NF-κB signaling. In this study, we asked if the non-oncogenic Tax-2 of the related HTLV-2 is still able to induce Fascin by using luciferase assays, immunoblot, and qPCR. We found that Tax-2 only slightly induces Fascin expression compared to Tax-1; however, both Tax-1 and Tax-2 comparably activated a 1.6 kb fragment in the human Fascin promoter including Tax-responsive elements. Furthermore, we identified a link between Tax-induced activity of the alternative NF-κB pathway and Fascin induction. While treatment with the second mitochondria-derived activator of caspases (SMAC)-mimetic AZD5582, a compound known to robustly activate alternative NF-κB signaling, did not induce Fascin, combination of AZD5582 with activation of classical NF-κB signaling by Tax-2 significantly induced Fascin expression. In conclusion, our data demonstrate that both classical and alternative NF-κB activity are necessary for strong Fascin induction by the viral Tax oncoproteins, thus, shedding new light on the regulation of Fascin in T-cells and during viral transformation.

A Panel of Eight miRNAs Is Deregulated in HTLV-2 Infected PBMCs and BJABGu Cell Line

“…Both HTLV-1 and HTLV-2 survive through a persistent clonal expansion of infected cells; however, unlike HTLV-1, HTLV-2 exhibits a predominant transformation of the CD8+ T cell subset, which harbors the majority of HTLV-2 proviral load [ 19 ]. Cellular immortalization in vivo, as well as viral pathogenesis, are primarily mediated by Tax-1 and Tax-2 transactivating proteins, whose effects on the cellular pathways are divergent [ 20 , 21 , 22 , 23 , 24 ]. Although Tax-1 and Tax-2 show an amino acid similarity of 85%, Tax-2 differs in recruiting host co-activators to enhance LTR transcription and signal transduction compared with Tax-1 [ 12 ].…”