HBZ upregulates myoferlin expression to facilitate HTLV-1 infection.

The complex retrovirus, human T-cell leukemia virus type 1 (HTLV-1), primarily infects CD4+ T-cells in vivo. Infectious spread within this cell population requires direct contact between virally-infected and target cells. The HTLV-1 accessory protein, HBZ, was recently shown to enhance HTLV-1 infection by activating intracellular adhesion molecule 1 (ICAM-1) expression, which promotes binding of infected cells to target cells and facilitates formation of a virological synapse. In this study we show that HBZ additionally enhances HTLV-1 infection by activating expression of myoferlin (MyoF), which functions in membrane fusion and repair and vesicle transport. Results from ChIP assays and quantitative reverse transcriptase PCR indicate that HBZ forms a complex with c-Jun or JunB at two enhancer sites within the MYOF gene and activates transcription through recruitment of the coactivator p300/CBP. In HTLV-1-infected T-cells, specific inhibition of MyoF using the drug, WJ460, or shRNA-mediated knockdown of MyoF reduced infection efficiency. This effect was associated with a decrease in cell adhesion and an intracellular reduction in the abundance of HTLV-1 envelope (Env) surface unit (SU) and transmembrane domain (TM). Lysosomal protease inhibitors partially restored SU levels in WJ460-treated cells, and SU localization to LAMP-2 sites was increased by MyoF knockdown, suggesting that MyoF restricts SU trafficking to lysosomes for degradation. Consistent with these effects, less SU was associated with cell-free virus particles. Together, these data suggest that MyoF contributes to HTLV-1 infection through modulation of Env trafficking and cell adhesion.

The splice 1 variant of HTLV-1 bZIP factor stabilizes c-Jun.

HBZ is expressed by the complex retrovirus, Human T-cell Leukemia Virus type 1, and implicated in pathological effects associated with viral infection. From the nucleus, HBZ alters gene expression by interacting with a variety of transcriptional regulatory proteins, among which is c-Jun. Previously, one of the three HBZ variants, HBZUS, was reported to decrease c-Jun expression by promoting its degradation. Here we show that another variant, HBZS1, produces the opposite effect. In the presence of HBZS1, c-Jun expression increases due to its stabilization. Our data suggest that this effect requires the ability of HBZS1 to interact with c-Jun. We provide evidence that HBZS1 inhibits the proteosomal degradation of c-Jun initiated by the Cop1-containing ubiquitin ligase complex. HBZS1 is the most abundant variant in HTLV-1-infected T-cells, and our data indicate that levels of c-Jun expression in infected cells are consistent with effects of HBZS1.