Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Lyda Hill Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun. 2022 Mar 1;13(1):1109. doi: 10.1038/s41467-022-28772-0.
Immune stimulation fuels cell signaling-transcriptional programs inducing biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states; however, the regulatory mechanisms are still unfolding. Here, we implemented a functional screen leveraging HIV-1's dependence on CD4 T cell signaling-transcriptional programs and discovered ADAP1 is an undescribed modulator of HIV-1 proviral fate. Specifically, we report ADAP1 (ArfGAP with dual PH domain-containing protein 1), a previously thought neuronal-restricted factor, is an amplifier of select T cell signaling programs. Using complementary biochemical and cellular assays, we demonstrate ADAP1 inducibly interacts with the immune signalosome to directly stimulate KRAS GTPase activity thereby augmenting T cell signaling through targeted activation of the ERK-AP-1 axis. Single cell transcriptomics analysis revealed loss of ADAP1 function blunts gene programs upon T cell stimulation consequently dampening latent HIV-1 reactivation. Our combined experimental approach defines ADAP1 as an unexpected tuner of T cell programs facilitating HIV-1 latency escape.
免疫刺激会引发细胞信号转导-转录程序，从而引发生物反应以清除感染病毒的细胞。然而，整合到宿主细胞染色质中的逆转录病毒，如 HIV-1，会利用这些程序在潜伏和重新激活状态之间切换；然而，调节机制仍在不断发展。在这里，我们实施了一项功能筛选，利用 HIV-1 对 CD4 T 细胞信号转导-转录程序的依赖性，并发现 ADAP1 是一种未被描述的 HIV-1 前病毒命运调节剂。具体来说，我们报告 ADAP1（具有双 PH 结构域的 ARF GAP 蛋白 1），以前被认为是神经元特异性因子，是选择 T 细胞信号程序的放大器。使用互补的生化和细胞测定法，我们证明 ADAP1 可诱导性地与免疫信号体相互作用，直接刺激 KRAS GTPase 活性，从而通过靶向激活 ERK-AP-1 轴增强 T 细胞信号。单细胞转录组学分析表明，ADAP1 功能丧失会在 T 细胞刺激时削弱基因程序，从而抑制潜伏 HIV-1 的重新激活。我们的综合实验方法将 ADAP1 定义为一种意外的 T 细胞程序调谐器，有助于 HIV-1 潜伏期逃逸。
