HBZ upregulates myoferlin expression to facilitate HTLV-1 infection.

Nicholas Polakowski, Md Abu Kawsar Sarker, Kimson Hoang, Georgina Boateng, Amanda W Rushing, Wesley Kendle, Claudine Pique, Patrick L Green, Amanda R Panfil, Isabelle Lemasson

PLoS pathogens 2023 Feb

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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. Copyright: © 2023 Polakowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Nicholas Polakowski, Md Abu Kawsar Sarker, Kimson Hoang, Georgina Boateng, Amanda W Rushing, Wesley Kendle, Claudine Pique, Patrick L Green, Amanda R Panfil, Isabelle Lemasson. HBZ upregulates myoferlin expression to facilitate HTLV-1 infection. PLoS pathogens. 2023 Feb;19(2):e1011202