Ghosh Anandita, Chandran Bala, Roy Arunava
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA.
Department of Interdisciplinary Oncology, LSU-LCMC Cancer Center, Louisiana State University Health, New Orleans, LA 70112, USA.
Viruses. 2025 Jun 28;17(7):921. doi: 10.3390/v17070921.
IFI16 is a well-characterized nuclear innate immune DNA sensor that detects foreign dsDNA, including herpesviral genomes, to activate the inflammasome and interferon pathways. Beyond immune signaling, IFI16 also functions as an antiviral restriction factor, promoting the silencing of invading viral genes through transcriptional and epigenetic mechanisms. We recently demonstrated another role of IFI16, in which it interacts with and recruits the class I histone deacetylases, HDAC1 and 2, to the KSHV latency protein LANA, modulating its acetylation and function. In this study, we asked whether these IFI16-HDAC1/2 interactions contribute to broader epigenetic regulation of the KSHV chromatin. Our findings reveal that IFI16 associates with and facilitates the recruitment of the NuRD and Sin3A co-repressor complexes-both multiprotein, HDAC1/2-containing chromatin regulators-on KSHV episomes. Depletion of IFI16 led to reductions in NuRD and Sin3A occupancy on viral chromatin, accompanied by increased histone acetylation at lytic gene promoters. These results suggest that IFI16 plays a critical role in recruiting or stabilizing these HDAC-containing co-repressor complexes on the KSHV genome, thereby enforcing transcriptional silencing of lytic genes and maintaining latency in KSHV. Our study expands the known functions of IFI16 and identifies a novel epigenetic mechanism by which it modulates herpesviral chromatin states.
IFI16是一种特征明确的核内先天性免疫DNA传感器，可检测包括疱疹病毒基因组在内的外源双链DNA，以激活炎性小体和干扰素信号通路。除了免疫信号传导外，IFI16还作为一种抗病毒限制因子，通过转录和表观遗传机制促进入侵病毒基因的沉默。我们最近证明了IFI16的另一个作用，即它与I类组蛋白去乙酰化酶HDAC1和2相互作用并将其招募到卡波西肉瘤相关疱疹病毒（KSHV）潜伏蛋白LANA上，调节其乙酰化和功能。在本研究中，我们探究了这些IFI16-HDAC1/2相互作用是否有助于对KSHV染色质进行更广泛的表观遗传调控。我们的研究结果表明，IFI16与NuRD和Sin3A共抑制复合物（两种含HDAC1/2的多蛋白染色质调节因子）结合并促进它们在KSHV附加体上的募集。IFI16的缺失导致NuRD和Sin3A在病毒染色质上的占有率降低，同时伴随着裂解基因启动子处组蛋白乙酰化增加。这些结果表明，IFI16在KSHV基因组上募集或稳定这些含HDAC的共抑制复合物中起关键作用，从而增强裂解基因的转录沉默并维持KSHV的潜伏状态。我们的研究扩展了IFI16的已知功能，并确定了一种调节疱疹病毒染色质状态的新表观遗传机制。
