IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation
IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation
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DOI：
10.1016/j.chom.2019.05.002
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发表时间：
2019-06-12
影响因子：
30.3
通讯作者：
Kirchhoff, Frank
中科院分区：
文献类型：
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作者：
Hotter, Dominik;Bosso, Matteo;Kirchhoff, Frank
干扰素γ诱导蛋白16（interferongamma-inducibleprotein 16，IFI 16）是逆转录病毒DNA中间体的免疫传感器。我们表明，IFI 16限制HIV-1独立的免疫感应结合和抑制宿主转录因子Sp1驱动病毒基因表达。这种抗逆转录病毒活性和结合Sp1的能力需要IFI 16的N-末端pyrin结构域和核定位，但不需要参与DNA结合的HIN结构域。高度流行的进化枝C HIV-1毒株对IFI 16的抗性更强，对Sp1的依赖性低于其他HIV-1亚型。此外，IFI 16或Mithramycin A抑制Sp1可抑制CD 4（+）T细胞中潜伏HIV-1的再活化。最后，IFI 16还抑制LINE-1的逆转录转座，已知LINE-1与Sp1接合，并且鼠IFI 16同源物限制小鼠中Friend逆转录病毒的复制。因此，IFI 16通过干扰Sp1依赖的基因表达来限制逆转录病毒和逆转录转座子，而逃避这种限制可能会促进HIV-1亚型C的传播。
The interferon gamma-inducible protein 16 (IFI16) is known as immune sensor of retroviral DNA intermediates. We show that IFI16 restricts HIV-1 independently of immune sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression. This antiretroviral activity and ability to bind Sp1 require the N-terminal pyrin domain and nuclear localization of IFI16, but not the HIN domains involved in DNA binding. Highly prevalent clade C HIV-1 strains are more resistant to IFI16 and less dependent on Sp1 than other HIV-1 subtypes. Furthermore, inhibition of Sp1 by IFI16 or pharmacologically by Mithramycin A suppresses reactivation of latent HIV-1 in CD4(+) T cells. Finally, IFI16 also inhibits retrotransposition of LINE-1, known to engage Sp1, and murine IFI16 homologs restrict Friend retrovirus replication in mice. Thus, IFI16 restricts retroviruses and retrotransposons by interfering with Sp1-dependent gene expression, and evasion from this restriction may facilitate spread of HIV-1 subtype C.