Department of Biochemistry and Molecular Biology, Molecular Epigenetics Group, LSI, University of British Columbia, Vancouver, B.C., Canada.
Commun Biol. 2023 Jan 23;6(1):86. doi: 10.1038/s42003-023-04484-z.
Binding of USF1/2 and TFII-I (RBF-2) at conserved sites flanking the HIV-1 LTR enhancer is essential for reactivation from latency in T cells, with TFII-I knockdown rendering the provirus insensitive to T cell signaling. We identified an interaction of TFII-I with the tripartite motif protein TRIM24, and these factors were found to be constitutively associated with the HIV-1 LTR. Similar to the effect of TFII-I depletion, loss of TRIM24 impaired reactivation of HIV-1 in response to T cell signaling. TRIM24 deficiency did not affect recruitment of RNA Pol II to the LTR promoter, but inhibited transcriptional elongation, an effect that was associated with decreased RNA Pol II CTD S2 phosphorylation and impaired recruitment of CDK9. A considerable number of genomic loci are co-occupied by TRIM24/TFII-I, and we found that TRIM24 deletion caused altered T cell immune response, an effect that is facilitated by TFII-I. These results demonstrate a role of TRIM24 for regulation of transcriptional elongation from the HIV-1 promoter, through its interaction with TFII-I, and by recruitment of P-TEFb. Furthermore, these factors co-regulate a significant proportion of genes involved in T cell immune response, consistent with tight coupling of HIV-1 transcriptional activation and T cell signaling.
USF1/2 和 TFII-I（RBF-2）与 HIV-1 LTR 增强子侧翼的保守位点结合对于 T 细胞潜伏感染的重新激活至关重要，TFII-I 的敲低使前病毒对 T 细胞信号不敏感。我们发现 TFII-I 与三肽基 motif 蛋白 TRIM24 相互作用，这些因子被发现与 HIV-1 LTR 持续相关。与 TFII-I 耗竭的效果相似，TRIM24 的缺失损害了 HIV-1 对 T 细胞信号的重新激活。TRIM24 缺陷不影响 RNA Pol II 向 LTR 启动子的募集，但抑制转录延伸，这种效应与 RNA Pol II CTD S2 磷酸化减少和 CDK9 的募集受损有关。相当数量的基因组位点被 TRIM24/TFII-I 共同占据，我们发现 TRIM24 缺失导致 T 细胞免疫反应改变，这种效应是由 TFII-I 介导的。这些结果表明，TRIM24 通过与 TFII-I 的相互作用以及 P-TEFb 的募集，在调节 HIV-1 启动子的转录延伸中发挥作用。此外，这些因子共同调节参与 T 细胞免疫反应的大量基因，这与 HIV-1 转录激活和 T 细胞信号的紧密偶联一致。
