Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-κB

Abstract

AbstractAdult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). The activation of NF-κB by Tax has been reported to play a crucial role in HTLV-1–induced transformation. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, is involved in both T cell proliferation and suppression of Tax-mediated viral gene transcription, suggesting that HBZ cooperates closely with Tax. In the present study, we observed that HBZ specifically suppressed NF-κB–driven transcription mediated by p65 (the classical pathway) without inhibiting the alternative NF-κB signaling pathway. In an immunoprecipitation assay, HBZ bound to p65 and diminished the DNA binding capacity of p65. In addition, HBZ induced p65 degradation through increasing the expression of the PDLIM2 gene, which encodes a ubiquitin E3 ligase for p65. Finally, HBZ actually repressed the transcription of some classical NF-κB target genes, such as IL-8, IL2RA, IRF4, VCAM-1, and VEGF. Selective suppression of the classical NF-κB pathway by HBZ renders the alternative NF-κB pathway predominant after activation of NF-κB by Tax or other stimuli, which might be critical for oncogenesis.