The HBZ gene, a key player in HTLV-1 pathogenesis

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and is also associated with a variety of lymphocyte-mediated diseases. The HTLV-1 basic leucine zipper (HBZ) gene, found to be consistently expressed in ATL, has recently been the subject of intensive research efforts. In this review, we summarize recent findings about HBZ and discuss its roles and functions not only in the virus life cycle, but also in HTLV-1 disease pathogenesis.

Figure 1

Structure of spliced and unspliced HBZ genes. The U5 and a part of R region of 3'LTR compose the promoter for the HBZ gene. The first exon of the spliced HBZ gene corresponds to the region that encodes the Rex responsive element (RxRE). The differences in the proteins derived from the spliced and the unspliced HBZ are 4 amino acids in the spliced HBZ and 7 amino acids in the unspliced HBZ.

Figure 2

Functional domains of HBZ protein. HBZ has three domains: activation, central and bZIP domains. The interactions with host factors and the functions of HBZ are summarized in this Figure.

Figure 3

Illustration of the expression and the activities of the HBZ RNA and protein. Viral basal level plus-strand transcription is activated by AP-1 (Jun/Fos dimers) which initially favors Tax expression (hooked arrow denotes CAP site). Tax interacts with CREB and p300/CBP and the Tax-response element (TRE; 3 black bars in the viral promoter) to transactivate plus-strand transcription initially, leading to more Tax expression. Minus strand transcription of HBZ initiates (hooked arrows denote CAP sites) at multiple sites in the 3' LTR (sHBZ) and within the tax gene (usHBZ). sHBZ transcription is activated by SP1 with minor activation by Tax at the TRE in the 3'LTR. HBZ protein directly interacts with CREB and p300/CBP suppressing Tax-mediated plus-strand transcription. HBZ directly binds the Jun family members. Binding to JunB sequesters HBZ into nuclear bodies and may promote its proteosomal degradation. HBZ directly binds c-Jun, blocks its DNA binding activity, and facilitates its proteosomal degradation. HBZ binding of JunB and c-Jun prevents their interaction with Fos repressing both viral and cellular AP-1 transcription. HBZ directly interacts with JunD, and in conjunction with SP1 activates JunD-mediated transcription which includes the human telomerase reverse transcriptase gene (hTERT). HBZ also interacts with the p65 NFκB subunit, promotes its proteosomal degradation, and blocks its interaction with the NFκB p50 subunit resulting in the suppression of the classical NFκB transcriptional activation pathway. HBZ mRNA increases the expression of E2F1 which promotes T-lymphocyte proliferation.