Hiyoshi Masateru, Eltalkhawy Youssef M, Abdelnaser Randa A, Ono Akira, Monde Kazuaki, Maeda Yosuke, Mahmoud Reem M, Takahashi Naofumi, Hatayama Yasuyoshi, Ryo Akihide, Nozuma Satoshi, Takashima Hiroshi, Kubota Ryuji, Suzu Shinya
Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, Tokyo, Japan.
Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
PLoS Pathog. 2025 Jan 27;21(1):e1012919. doi: 10.1371/journal.ppat.1012919. eCollection 2025 Jan.
We have demonstrated that the cellular protein M-Sec promotes the transmission of human T-cell leukemia virus type 1 (HTLV-1) in vitro and in vivo. Here, we show how HTLV-1 utilizes M-Sec for its efficient transmission. HTLV-1-infected CD4+ T cells expressed M-Sec at a higher level than uninfected CD4+ T cells. The ex vivo culture of the infected cells upregulated the expression of M-Sec, the level of which was sustained for a long time. The viral structural protein Gag is distributed in a punctate pattern in cells. M-Sec promoted the accumulation of large intracellular Gag puncta. This accumulation was dependent on phosphatidylinositol 4,5-bisphosphate (PIP2), since it was lost upon the removal of PIP2 binding motifs in M-Sec or the depletion of cellular PIP2. The viral envelope protein Env co-localized with the large Gag puncta induced by M-Sec. Furthermore, viral particles produced by M-Sec-expressing cells contained a higher amount of Env. Given that M-Sec alters the cellular distribution of PIP2, these results suggest that M-Sec promotes the formation of infectious viral particles through PIP2. Since the expression of M-Sec is mediated by HTLV-1 Tax protein, M-Sec appears to function in a positive feedback loop that ensures efficient HTLV-1 transmission.
我们已经证明,细胞蛋白M-Sec在体外和体内均能促进1型人类T细胞白血病病毒(HTLV-1)的传播。在此,我们展示了HTLV-1如何利用M-Sec实现其高效传播。HTLV-1感染的CD4+ T细胞比未感染的CD4+ T细胞表达更高水平的M-Sec。感染细胞的体外培养上调了M-Sec的表达,且该水平能长时间维持。病毒结构蛋白Gag在细胞中呈点状分布。M-Sec促进了细胞内大的Gag点状聚集物的积累。这种积累依赖于磷脂酰肌醇4,5-二磷酸(PIP2),因为在去除M-Sec中的PIP2结合基序或细胞内PIP2耗竭后,这种积累就会消失。病毒包膜蛋白Env与M-Sec诱导形成的大的Gag点状聚集物共定位。此外,表达M-Sec的细胞产生的病毒颗粒含有更高量的Env。鉴于M-Sec改变了PIP2的细胞分布,这些结果表明M-Sec通过PIP2促进感染性病毒颗粒的形成。由于M-Sec的表达由HTLV-1 Tax蛋白介导,M-Sec似乎在一个确保HTLV-1高效传播的正反馈回路中发挥作用。