Paz Sean, Krainer Adrian R, Caputi Massimo
Nucleic Acids Res. 2014 Dec 16;42(22):13812-23. doi: 10.1093/nar/gku1170.
Efficient transcription of the HIV-1 genome is regulated by Tat, which recruits P-TEFb from the 7SK small nuclear ribonucleoprotein (snRNP) and other nucleoplasmic complexes to phosphorylate RNA polymerase II and other factors associated with the transcription complex. Although Tat activity is dependent on its binding to the viral TAR sequence, little is known about the cellular factors that might also assemble onto this region of the viral transcript. Here, we report that the splicing factor SRSF1 (SF2/ASF) and Tat recognize overlapping sequences within TAR and the 7SK RNA. SRSF1 expression can inhibit Tat transactivation by directly competing for its binding to TAR. Additionally, we provide evidence that SRSF1 can increase the basal level of viral transcription in the absence of Tat. We propose that SRSF1 activates transcription in the early stages of viral infection by recruiting P-TEFb to TAR from the 7SK snRNP. Whereas in the later stages, Tat substitutes for SRSF1 by promoting release of the stalled polymerase and more efficient transcriptional elongation.
HIV-1基因组的高效转录受Tat调控,Tat从7SK小核核糖核蛋白(snRNP)和其他核质复合物中募集P-TEFb,使RNA聚合酶II及与转录复合物相关的其他因子磷酸化。尽管Tat的活性依赖于其与病毒TAR序列的结合,但对于可能也组装到病毒转录本该区域的细胞因子却知之甚少。在此,我们报告剪接因子SRSF1(SF2/ASF)和Tat识别TAR和7SK RNA内的重叠序列。SRSF1的表达可通过直接竞争其与TAR的结合来抑制Tat反式激活。此外,我们提供证据表明,在没有Tat的情况下,SRSF1可增加病毒转录的基础水平。我们提出,SRSF1在病毒感染早期通过从7SK snRNP募集P-TEFb到TAR来激活转录。而在后期,Tat通过促进停滞的聚合酶释放和更有效的转录延伸来替代SRSF1。