Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis

Abstract

Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus responsible for the development of adult T-cell leukemia (ATL). Although HTLV-1 harbors an oncogene, tax, that transforms T cells in vitro and induces leukemia in transgenic mice, tax expression is frequently disrupted in ATL, making the oncogenesis of ATL a bit mysterious. The HTLV-1 bZIP factor (HBZ) gene was discovered in 2002 and has been found to promote T-cell proliferation and cause lymphoma in transgenic mice. Thus HBZ has become a novel hotspot of HTLV-1 research. This review summarizes the current findings on HBZ with a special focus on its potential links to the oncogenesis of ATL. We propose viewing HBZ as a critical contributing factor in ATL development.

Keywords: HBZ; HTLV-1; Regulatory T cell; Tax; Viral oncogenesis.

Fig. 1

HTLV-1 provirus, mRNAs and proteins. HTLV-1 provirus is shown on top in blue with both LTRs painted in brown. Below, the transcripts and proteins encoded by a complete HTLV-1 provirus are shown. Sense transcripts are portrayed as black arrows with arrowheads pointing to the right, while antisense transcripts run in the opposite direction. Spliced exons are shown in solid black lines while introns are shown as dotted lines. Proteins derived from respective mRNAs are shown as empty squares

Fig. 2

Cellular proteins that interact with HBZ. The three domains of sHBZ are portrayed as squares in three different colors while the cellular binding partners of HBZ are demonstrated as squircles with colors corresponding to that of AD, CD or bZIP domain of HBZ that they interact with. Cellular proteins that bind to more than one domain of HBZ are painted in multiple colors whereas those lacking such information are painted in dark grey. The major pathways that these interactions have impact on, either positive (+) or negative (−), are noted close to respective cellular proteins while more detailed description can be found in the text. Some of the interactions are not discussed in the text due to space limitations, which include 26s proteasome [93], CENP-B [94], C/EBPα [95] and IRF-1 [96]. For Foxp3, HBZ enhances transcription from the Foxp3 promoter (Treg differentiation: diff.) while it suppresses function of Foxp3 (Treg function: func.)

Fig. 3

HBZ viewed from a cancer hallmarks perspective. Ten cancer hallmarks are listed and painted in different colors on the right [92]. White boxes on the left briefly outline functions of HBZ that relate to the corresponding cancer hallmark on the right. HBZ RNA-related functions are marked in red