Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved RNA decay mechanism that has emerged as a potent cell-intrinsic restriction mechanism of retroviruses and positive-strand RNA viruses. However, whether NMD is capable of restricting DNA viruses is not known. The DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma and primary effusion lymphoma (PEL). Here, we demonstrate that NMD restricts KSHV lytic reactivation. Leveraging high-throughput transcriptomics we identify NMD targets transcriptome-wide in PEL cells and identify host and viral RNAs as substrates. Moreover, we identified an NMD-regulated link between activation of the unfolded protein response and transcriptional activation of the main KSHV transcription factor RTA, itself an NMD target. Collectively, our study describes an intricate relationship between cellular targets of an RNA quality control pathway and KSHV lytic gene expression, and demonstrates that NMD can function as a cell intrinsic restriction mechanism acting upon DNA viruses.

无意义介导的mRNA衰变（NMD）是一种进化上保守的RNA衰变机制，已成为逆转录病毒和正链RNA病毒的一种强大的细胞内在限制性机制。但是，还不清楚NMD是否能够限制DNA病毒。DNA病毒卡波西氏肉瘤相关疱疹病毒（KSHV）是卡波西氏肉瘤和原发渗出性淋巴瘤（PEL）的病原体。在这里，我们证明NMD限制了KSHV裂解再激活。利用高通量转录组学，我们可以确定PEL细胞中整个转录组的NMD靶标​​，并将宿主和病毒RNA鉴定为底物。此外，我们确定了NMD调控的展开的蛋白质反应的激活和主要KSHV转录因子RTA，本身是NMD目标的转录激活之间的联系。总的来说，