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HTLV-1-mediated dysregulation of the Wnt pathways: roles of Tax and HBZ

Human T cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Dysregulations of cellular signaling pathways have been considered to be important strategies for HTLV-1 induced leukemogenesis. In this study, we found that a Wnt pathway-related protein, Dishevelled (Dvl)-associating protein with a high frequency of leucine residues (DAPLE), could be associated with Tax to activate the canonical Wnt signaling. However, in the downstream of the pathway, T-cell factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1), which are two transcription factors mainly expressed in T-cells, could interact with Tax and suppress its transactivating ability. We further found virus production was greatly inhibited by TCF1/LEF1. Due to the high expression of TCF1/LEF1 in the thymus and their significant downregulation upon T-cell activation, we suspect TCF1/LEF1 may contribute to the HTLV-1 tropism on activated mature T-cells. On the other hand, HTLV-1 bZIP factor (HBZ) markedly suppressed canonical Wnt activation through targeting both TCF1 and LEF1. As a result, the canonical Wnt pathway was not activated in HTLV-1-infected cells, whereas the representative of noncanonical Wnt ligands, Wnt5a, which antagonizes canonical Wnt signaling, was overexpressed in HTLV-1 infected cells. Further experiments revealed HBZ could induce Wnt5a expression through activation of the TGF-β pathway. Importantly, knocking down of Wnt5a in HTLV-1-infected cells repressed cellular proliferation and migration. By suppressing the canonical and enhancing the noncanonical Wnt pathway, HBZ is likely able to generate a favorable environment for HTLV-1 infection and persistence.

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Correspondence to Jun-ichiro Yasunaga.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated.

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Ma, G., Yasunaga, Ji., Fan, J. et al. HTLV-1-mediated dysregulation of the Wnt pathways: roles of Tax and HBZ. Retrovirology 11 (Suppl 1), P91 (2014).

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