Human T Cell Leukemia Virus Type I Tax--Induced IκB-ζ Modulates Tax-Dependent and Tax-Independent Gene Expression in T Cells.

Human T cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL) and various inflammatory disorders including HTLV-I--associated myelopathy/tropical spastic paraparesis. HTLV-I oncoprotein Tax is known to cause permanent activation of many cellular transcription factors including nuclear factor-κB(NF-κB), cyclic adenosine 3',5'-monophosphate response element--binding protein, and activator protein 1 (AP-1). Here, we show that NF-κB--binding cofactor inhibitor of NF-κB-ζ (IκB-ζ) is constitutively expressed in HTLV-I--infected T cell lines and ATL cells, and Tax transactivates the IκB-ζ gene, mainly through NF-κB. Microarray analysis of IκB-ζ--expressing uninfected T cells demonstrated that IκB-ζ induced the expression of NF-κB-- and interferon-regulatory genes such as B cell CLL/lymphoma 3 (Bcl3), guanylate-binding protein 1,and signal transducer and activator of transcription 1. The transcriptional activation domain, nuclear localization signal, and NF-κB--binding domain of IκB-ζ were required for Bcl3 induction, and IκB-ζ synergistically enhanced Tax-induced Bcl3 transactivation in an NF-κB--dependent manner. Interestingly, IκB-ζ inhibited Tax-induced NF-κB, AP-1 activation, and HTLV-I transcription. Furthermore, IκB-ζ interacted with Tax in vitro and this interaction was also observed in an HTLV-I--transformed T cell line. These results suggest that IκB-ζ modulates Tax-dependent and Tax-independent gene transcription in T cells. The function of IκB-ζ may be of significance in ATL genesis and pathogenesis of HTLV-I--associated diseases. [ABSTRACT FROM AUTHOR]