Endogenous retroviruses (ERVs) have accumulated in vertebrate genomes and contribute to the complexity of gene regulation. KAP1 represses ERVs during development by its recruitment to their repetitive sequences through KRAB zinc‐finger proteins (KZNFs), but little is known about the regulation of ERVs in adult tissues. We observed that KAP1 repression of HERVK14C was conserved in differentiated human cells and performed KAP1 knockout to obtain an overview of KAP1 function. Our results show that KAP1 represses ERVs (including HERV‐T and HERV‐S) and ZNF genes, both of which overlap with KAP1 binding sites and H3K9me3 in multiple cell types. Furthermore, this pathway is functionally conserved in adult human peripheral blood mononuclear cells. Cytosine methylation that acts on KAP1 regulated loci is necessary to prevent an interferon response, and KAP1‐depletion leads to activation of some interferon‐stimulated genes. Finally, loss of KAP1 leads to a decrease in H3K9me3 enrichment at ERVs and ZNF genes and an RNA‐sensing response mediated through MAVS signaling. These data indicate that the KAP1‐KZNF pathway contributes to genome stability and innate immune control in adult human cells.

内源性逆转录病毒（ ERV ）在脊椎动物基因组中积累，并导致基因调控的复杂性。 KAP 1 在发育过程中通过KRAB锌指蛋白 ( KZNF ) 招募到其重复序列来抑制ERV ，但人们对成人组织中ERV的调节知之甚少。我们观察到KAP 1 对HERVK 14C 的抑制在分化的人类细胞中是保守的，并进行KAP 1 敲除以获得KAP 1 功能的概述。我们的结果表明， KAP 1 抑制ERV s（包括HERV ‐T 和HERV ‐S）和 ZNF 基因，这两个基因与多种细胞类型中的KAP 1 结合位点和 H3K9me3 重叠。此外，该途径在成人外周血单核细胞中功能保守。作用于KAP 1 调节位点的胞嘧啶甲基化对于防止干扰素反应是必要的， KAP 1 缺失会导致一些干扰素刺激基因的激活。最后， KAP 1 的缺失导致ERV和 ZNF 基因处的 H3K9me3 富集度以及通过MAVS信号传导介导的RNA传感反应减少。这些数据表明KAP 1- KZNF通路有助于成人细胞的基因组稳定性和先天免疫控制。