Gladstone Institute of Virology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Tetrad Graduate Program, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell Rep. 2023 Mar 28;42(3):112234. doi: 10.1016/j.celrep.2023.112234. Epub 2023 Mar 9.
A successful HIV-1 cure strategy may require enhancing HIV-1 latency to silence HIV-1 transcription. Modulators of gene expression show promise as latency-promoting agents in vitro and in vivo. Here, we identify Su(var)3-9, enhancer-of-zeste, and trithorax (SET) and myeloid, Nervy, and DEAF-1 (MYND) domain-containing protein 5 (SMYD5) as a host factor required for HIV-1 transcription. SMYD5 is expressed in CD4 T cells and activates the HIV-1 promoter with or without the viral Tat protein, while knockdown of SMYD5 decreases HIV-1 transcription in cell lines and primary T cells. SMYD5 associates in vivo with the HIV-1 promoter and binds the HIV trans-activation response (TAR) element RNA and Tat. Tat is methylated by SMYD5 in vitro, and in cells expressing Tat, SMYD5 protein levels are increased. The latter requires expression of the Tat cofactor and ubiquitin-specific peptidase 11 (USP11). We propose that SMYD5 is a host activator of HIV-1 transcription stabilized by Tat and USP11 and, together with USP11, a possible target for latency-promoting therapy.
一种成功的 HIV-1 治愈策略可能需要增强 HIV-1 潜伏期以沉默 HIV-1 转录。基因表达调节剂在体外和体内均显示出作为促进潜伏期的试剂的潜力。在这里，我们确定 Su(var)3-9、增强子-of-zeste 和 trithorax (SET) 以及髓样、Nervy 和 DEAF-1 (MYND) 结构域包含蛋白 5 (SMYD5) 是 HIV-1 转录所需的宿主因子。SMYD5 在 CD4 T 细胞中表达，并在有或没有病毒 Tat 蛋白的情况下激活 HIV-1 启动子，而 SMYD5 的敲低会降低细胞系和原代 T 细胞中的 HIV-1 转录。SMYD5 在体内与 HIV-1 启动子结合，并与 HIV 反式激活反应 (TAR) 元件 RNA 和 Tat 结合。Tat 在体外被 SMYD5 甲基化，在表达 Tat 的细胞中，SMYD5 蛋白水平增加。后者需要 Tat 共因子和泛素特异性肽酶 11 (USP11) 的表达。我们提出，SMYD5 是 HIV-1 转录的宿主激活剂，由 Tat 和 USP11 稳定，并与 USP11 一起，是促进潜伏期治疗的可能靶点。
